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Machine Learning Discoveries of DNA Repair-X Synergy in ETC-1922159 Treated Colorectal Cancer Cells

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Advances in Colorectal Cancer Therapy

Submitted:

05 September 2024

Posted:

12 September 2024

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Abstract
Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combinations of factors/genes/proteins that might be affecting the pathway under certain conditions. In colorectal cancer (CRC) cells treated with ETC-1922159, many genes were found up and down regu- lated, individually. A recently developed search engine ranked combinations of DNA repair gene-X (X, a particular gene/protein) at 2nd order level after drug administration. These rankings reveal which Wnt-X combinations might be working synergistically in CRC. If found true, oncologists can further test the combination of interest in wet lab and determine the mechanism of functioning between the Wnt and X. In this re- search work, we cover combinations of RAD with X-ray repair cross complementing (XRCC) family, 5’-3’ exoribonuclease 2 (XRN2), NFKB repressing factor (NKRF), B cell CLL/lymphoma (BCL) family, exosome component (EXOSC) family, FA comple- mentation group (FANC) family and XRCC with EXOSC.
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Subject: Computer Science and Mathematics  -   Mathematical and Computational Biology

1. Introduction

In the unpublished preprint Sinha [1], a frame work of a search engine was developed which can rank combinations of factors (genes/proteins) in a signaling pathway. Such combinations are of import due to the vast search space in which they exist and the difficulty to find them. The search engine facilitates in prioritizing the combinations as ranked biological hypotheses which the biologists might want to test in wet lab, to know if a synergistic combination is prevalent in a signaling pathway, in a direct or indirect manner. Interested readers are advised to go through unpublished preprints Sinha [1] and Sinha [2] for details regarding the search engine and the discoveries mentioned in there.

2. Materials and Methods

2.1. Combinatorial Search Problem and a Possible Solution

The issue of combinatorial search problem and a possible solution has been addressed in Sinha [3] and Sinha [2]. The details of the methodology of this manuscript have been explained in great detail in Sinha [3] & its application in Sinha [2]. Readers are requested to go through the same for gaining deeper insight into the working of the pipeline and its use of published data set generated after administration of ETC-1922159. In order to understand the significance of the solution proposed to the problem of combinatorial search that the biologists face in revealing unknown biological search problem, these works are of importance.
Briefly, from Sinha [2], the pipleline works by computing sensitivity indicies for each of these unique combinations and then vectorising these indices to connote and form discriminative feature vector for each combination. Since each combination is unique, the training and the test data are same. In the training data, the combinations are arranged and ranks from 1 to n are assigned. The ranking algorithm then learns the patterns from these combinations/sensitivity index vectors. Next the learned model is used to rank the test data by generating the ranking score for each of the unique combination. Sorting these shuffled scores of test data leads to prioritization of the combinations. Joachims [4] show an example of applying learned model to training data (same as the test data) in https://www.cs.cornell.edu/people/tj/svm_light/svm_rank.html. Note that these combinations are now ranked and give the biologists a chance to narrow down their focus on crucial biological hypotheses in the form of combinations which the biologists might want to test. Analogous to the webpage search engine, where the click of a button for a few key-words leads to a ranked list of web links, the pipeline uses sensitivity indices as an indicator of the strength of the influence of factors or their combinations, as a criteria to rank the combinations.

3. Results & Discussion

3.1. DNA Repair Related Synergies

3.1.1. XRCC - RAD Cross Family Analysis

X-ray repair cross-complementing protein (XRCC) plays major role in DNA repair process, especially in Double Strand Repair (DBS) Thacker and Zdzienicka [5] and Thacker and Zdzienicka [6]. Sultana et al. [7] observe that ataxia telangiectasia mutated and RAD3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells. Della-Maria et al. [8] observe that human Mre11/human RAD50/Nbs1 and DNA ligase III α /XRCC1 protein complexes act together in an alternative nonhomologous end joining pathway. These findings along with multiple published work indicate the joint synergy of XRCC - RAD family. In colorectal cancer cell lines treated with ETC-1922159, both XRCC and RAD members were found to be down regulated. The search engine gave the 2nd order synergies between XRCC - RAD families, low numerical valued ranks to signify plausible synergistic down regulations that might not have been explored. Table 1 shows the rankings of RAD family w.r.t XRCC family and Table 2 shows the rankings of the XRCC family w.r.t RAD family. In Table 1 we found RAD-18/51/51AP1/51C/54B/54L to be down regulated w.r.t XRCC1. These are reflected with rankings of 1027 (laplace), 456 (linear) and 1355 (rbf) for RAD-18 - XRCC1; 282 (laplace), 365 (linear) and 1003 (rbf) for RAD51 - XRCC1; 753 (laplace), 5 (linear) and 27 (rbf) for RAD51AP1 - XRCC1; 337 (laplace), 111 (linear) and 968 (rbf) for RAD51C - XRCC1; 175 (laplace), 224 (linear) and 78 (rbf) for RAD54B - XRCC1; and 327 (laplace), 889 (linear) and 709 (rbf) for RAD54L - XRCC1. RAD-18/51/51AP1/51C/54B/54L were also found to be down regulated w.r.t XRCC2. These are reflected in 1388 (laplace), 847 (linear) and 765 (rbf) for XRCC2 - RAD18; 1247 (laplace), 1033 (linear) and 629 (rbf) for XRCC2 - RAD51; 302 (laplace); 247 (linear) and 42 (rbf) for XRCC2 - RAD51AP1; 1079 (laplace), 674 (linear) and 323 (rbf) for XRCC2 - RAD51C; 387 (laplace), 566 (linear) and 506 (rbf) for XRCC2 - RAD54B; and 976 (laplace), 918 (linear) and 847 (rbf) for XRCC2 - RAD54L. RAD-18/51/51AP1/51C/54B/54L were found to be down regulated with w.r.t XRCC6. These are reflected in 541 (laplace), 25 (linear) and 1068 (rbf) for RAD18 - XRCC6; 608 (laplace), 425 (linear) and 900 (rbf) for RAD51 - XRCC6; 216 (laplace), 67 (linear) and 83 (rbf) for RAD51AP1 - XRCC6; 426 (laplace), 865 (linear) and 503 (rbf) for RAD51C - XRCC6; 3 (laplace), 610 (linear) and 112 (rbf) for RAD54B - XRCC6; and 85 (laplace), 252 (linear) and 432 (rbf) for RAD54L - XRCC6. RAD-1/18/50/51/51AP1/51C/54B/54L were found to be down regulated w.r.t XRCC6BP1. These are reflected in 1167 (laplace) and 308 (rbf) for RAD1 - XRCC6BP1; 656 (linear) and 1612 (rbf) for RAD18 - XRCC6BP1; 1302 (laplace) and 328 (rbf) for XRCC6BP1 - RAD50; 435 (laplace), 495 (linear) and 1275 (rbf) for RAD51 - XRCC6BP1; 81 (laplace), 177 (linear) and 73 (rbf) for RAD51AP1 - XRCC6BP1; 645 (laplace), 1366 (linear) and 1414 (rbf) for RAD51C - XRCC6BP1; 154 (laplace), 693 (linear) and 1398 (rbf) for RAD54B - XRCC6BP1; and 420 (linear) and 1060 (rbf) for RAD54L - XRCC6BP1;
In Table 2 we found XRCC-2/6BP1 to be down regulated w.r.t RAD1. These are reflected in 62 (laplace), 498 (linear) and 1231 (rbf) for RAD1 - XRCC2; and 764 (laplace) and 1325 (rbf) for RAD1 - XRCC6BP1. XRCC-1/2/6 were found to be down regulated with w.r.t RAD18. These are reflected in 927 (laplace) and 200 (rbf) for RAD18 - XRCC1; 506 (laplace) and 1517 (rbf) for RAD18 - XRCC2; and 279 (laplace) and 804 (rbf) for RAD18 - XRCC6; XRCC-2/6BP1 were found to be down regulated w.r.t RAD50. These are reflected in rankings of 53 (laplace), 244 (linear) and 147 (rbf) for XRCC-2 - RAD50; and 1375 (linear) and 1366 (rbf) for RAD50 - XRCC6BP1. XRCC-6/6BP1 were found to be down regulated w.r.t RAD51; These are reflected in rankings of 80 (laplace) and 1244 (linear) for XRCC6 - RAD51; and 792 (laplace), 951 (linear) and 1595 (rbf) for XRCC6BP1 - RAD51. XRCC-2/6BP1 were found to be down regulated w.r.t RAD51AP1. These were reflected in 78 (laplace), 112 (linear) and 351 (rbf) for XRCC2 - RAD51AP1; and 936 (linear) and 974 (rbf) for XRCC6BP1 - RAD51AP1; XRCC2 was found to be down regulated w.r.t RAD51C. This are reflected in 1695 (laplace), 932 (linear) and 520 (rbf) for XRCC2 - RAD51C. XRCC2 was found to be down regulated w.r.t RAD54B. This is reflected in rankings of 1554 (laplace), 744 (linear) and 620 (rbf) for XRCC2 - RAD54B. XRCC-1/2/6/6BP1 were found to be down regulated w.r.t RAD54L. These are reflected in rankings of 657 (linear) and 525 (rbf) for XRCC1 - RAD54L; 167 (laplace) and 565 (rbf) for XRCC2 - RAD54L; 496 (linear) and 1247 (rbf) for XRCC6 - RAD54L; and 1389 (laplace), 1227 (linear) and 1454 (rbf) for RAD54L - XRCC6BP1;
Table 3 shows the derived influences which can be represented graphically, with the following influences - • RAD w.r.t XRCC with RAD-18/51/51AP1/51C/54B/54L < − XRCC1; RAD-18/51/51AP1/51C/54B/54L < − XRCC2; RAD-18/51/51AP1/51C/54B/54L < − XRCC6 and RAD-1/18/50/51/51AP1/51C/54B/54L < − XRCC6BP1; •; XRCC w.r.t RAD with RAD1 − > XRCC-2/6BP1; RAD18 − > XRCC-1/2/6; RAD50 − > XRCC-2/6BP1; RAD51 − > XRCC-6/6BP1; RAD51AP1 − > XRCC-2/6BP1; RAD51C − > XRCC-2; RAD54B − > XRCC-2; RAD54L − > XRCC-1/2/6/6BP1;

3.1.2. XRN2 - RAD Cross Family Analysis

XRN2 (5’-3’ exoribonuclease 2) is involved in RNA synthesis/trafficking and termination. Morales et al. [9] observe that XRN2 links transcription termination to DNA damage and replication stress. They found an increase in the amount of RAD51 foci in shXRN2 cells compared to controls, suggesting that cells depleted of XRN2 are subjected to an increased level of basal DNA damage and show that loss of XRN2 also leads to the focal accumulation of several factors required for homologous recombination, such as ATM, BRCA1 and RAD51. This definitely shows that there is synergy between the XRN2 and RAD51. We found that both the XRN2 and RAD families were down regulated in CRC cell after ETC-1922159 treatment. The search engine gave rankings to the combinations of the XRN2 and RAD family members with low numerical valued in silico ranks. Table 4 shows the rankings of XRN2 w.r.t RAD family and vice versa. Following this is the derived influences in Table 5. We find RAD-51AP1/51/54L/51C/18/54B to be down regulated w.r.t XRN2. These are reflected in rankings of 340 (laplace), 545 (linear) and 290 (rbf) for RAD51AP1 - XRN2; 387 (laplace), 560 (linear) and 605 (rbf) for XRN2 - RAD51; 594 (laplace), 827 (linear) and 879 (rbf) for XRN2 - RAD54L; 639 (laplace), 1236 (linear) and 745 (rbf) for XRN2 - RAD51C; 794 (laplace), 688 (linear) and 804 (rbf) for XRN2 - RAD18; 255 (linear) and 122 (rbf) for XRN2 - RAD1 and 951 (laplace), 165 (linear) and 34 (rbf) for XRN2 - RAD54B; On the other hand, XRN2 was found to be down regulated w.r.t RAD family. These are reflected in rankings of 255 (laplace) and 122 (rbf) for XRN2 - RAD1; 1256 (linear) and 852 (rbf) for XRN2 - RAD51AP1; 1541 (laplace) and 1246 (linear) for XRN2 - RAD54L and 1037 (laplace) and 1777 (linear) for XRN2 - RAD51C. Graphical depiction of XRN2 and RAD family dependencies is shown as • RAD w.r.t XRN2 with XRN2 − > RAD-51AP1/51/54L/51C/18/54B and • XRN2 w.r.t RAD with XRN2 < − RAD1; XRN2 < − RAD51AP1; XRN2 < − RAD54L; XRN2 < − RAD51C;
Table 5 shows the derived influences which can be represented graphically, with the following influences - • RAD w.r.t XRN2 with XRN2 − > RAD-51AP1/51/54L/51C/18/54B; and • XRN2 w.r.t RAD with XRN2 < − RAD-1/51AP1/54L/51C.

3.1.3. NKRF - RAD Cross Family Analysis

Not much is known about the NKRF (NF- κ B-repressing factor) and RAD members. We found the combinations to be down regulated by the search engine between NKRF and RAD family. Table 6 shows the rankings of NKRF and RAD family. We found NKRF down regulated w.r.t RAD family. These are reflected in rankings of 1724 (laplace), 1642 (linear) and 649 (rbf) for RAD51AP1 < − NKRF; 982 (laplace), 1724 (linear) and 1352 (rbf) RAD51 < − NKRF; 1727 (laplace), 1387 (linear) and 1120 (rbf) for RAD54L < − NKRF; 1568 (laplace), 472 (linear) and 1505 (rbf) for RAD51C < − NKRF; 1508 (laplace), 615 (linear) and 405 (rbf) for RAD18 < − NKRF; and 1476 (laplace), 1189 (linear) and 1534 (rbf) for RAD54B < − NKRF;
Also, we found RAD family to be down regulated w.r.t NKRF. These are reflected in rankings of 157 (laplace) and 553 (linear) for RAD51AP1 - NKRF; 439 (laplace), 1441 (linear) and 1606 (rbf) for RAD51 - NKRF; 117 (laplace), 1175 (linear) and 1415 (rbf) for RAD54L - NKRF; 418 (laplace), and 1653 (rbf) for RAD51C - NKRF; 164 (laplace) and 1509 (rbf) for RAD18 - NKRF; 1391 (laplace), 1115 (linear) and 735 (rbf) NKRF - RAD1; 1354 (laplace), 851 (linear) and 824 (rbf) for NKRF - RAD50;
Table 7 shows the derived influences which can be represented graphically, with the following influences - • RAD w.r.t NKRF with RAD51AP1 < − NKRF; RAD51 < − NKRF; RAD54L < − NKRF; RAD51C < − NKRF; RAD18 < − NKRF; RAD1 < − NKRF; RAD54B < − NKRF and • NKRF w.r.t RAD with RAD51AP1 − > NKRF; RAD51 − > NKRF; RAD54L − > NKRF; RAD51C − > NKRF; RAD18 − > NKRF; NKRF − > RAD1; NKRF − > RAD50.

3.1.4. RAD - BCL Cross Family Analysis

Saintigny et al. [10] show a specific role of BCL2 in suppression of the RAD51 recombination pathway. They observe that BCL2 consistently inhibits recombination stimulated by RAD51 overexpression and alters RAD51 protein by post-translation modification. Based on the findings that CARD9 and BCL10 acted together to activate NF-kB following cytosolic DNA sensing, Meng et al. [11] demonstrated that BCL10 was recruited to the dsDNA–RAD50 complexes in a CARD9-dependent manner. These mechanisms point to a synergy between BCL and RAD family. In CRC cells treated with ETC-1922159, BCL and RAD family members were found to be down regulated. The search engine alloted the combinations of RAD and BCL low numerical valued ranks pointing to possible synergistic down regulations. Table 8 shows rankings of BCL and RAD w.r.t to each other. The left half of the table points to rankings of BCL family w.r.t RAD family. The right half of the table points to rankings of RAD family w.r.t BCL family.
On the left side, BCL2L12 was found to be down regulated w.r.t RAD-1/18/50/51/51C/54B/54L. These are reflected in rankings of 1530 (linear) and 1401 (rbf) for RAD1 - BCL2L12; 675 (laplace) and 1312 (rbf) for RAD18 - BCL2L12; 1151 (linear) and 929 (rbf) for RAD50 - BCL2L12; 1234 (laplace) and 1334 (linear) for RAD51 - BCL2L12; 1561 (laplace) and 1647 (rbf) for RAD51C - BCL2L12; 1329 (linear) and 1625 (rbf) for RAD54B - BCL2L12, and 821 (linear) and 210 (rbf) for RAD54L - BCL2L12; BCL6B was found to be down regulated w.r.t RAD-1/18/50/51/51AP1/51C/54B/54L. 194 (laplace), 481 (linear) and 102 (rbf) for RAD1 - BCL6B; 176 (linear) and 929 (rbf) for RAD18 - BCL6B; 860 (laplace), 87 (linear) and 74 (rbf) for RAD50 - BCL6B; 263 (linear) and 58 (rbf) for RAD51 - BCL6B; 723 (laplace), 428 (linear) and 579 (rbf) for RAD51AP1 - BCL6B; 660 (laplace), 521 (linear) and 1609 (rbf) for RAD51C - BCL6B; 708 (laplace), 596 (linear) and 647 (rbf) for RAD54B - BCL6B; and 108 (laplace) and 1326 (rbf) for RAD54L - BCL6B; BCL7A was found to be down regulated w.r.t RAD-1/18/50/51/54L. These are reflected in rankings of 690 (laplace) and 1202 (rbf) for BCL7A - RAD1; 385 (laplace) and 185 (rbf) for BCL7A - RAD18; 137 (laplace), 601 (linear) and 41 (rbf) for RAD50 - BCL7A; 514 (laplace) and 1694 (linear) for BCL7A - RAD51; 1519 (laplace), 418 (linear) and 842 (rbf) for RAD54L - BCL7A; BCL9 was found to be down regulated w.r.t RAD-18/51/51C/54L. These are reflected in rankings for 461 (laplace) and 1453 (linear) for RAD18 - BCL9; 1143 (linear) and 95 (rbf) for RAD51 - BCL9; 956 (laplace) and 376 (rbf) for RAD51C - BCL9; 1450 (laplace), 1096 (linear) and 400 (rbf) for RAD54L - BCL9; BCL11A was found to be down regulated w.r.t RAD-1/18/50/51/51AP1/51C/54B. These are reflected in rankings of 1069 (laplace), 507 (linear) and 1267 (rbf) for RAD1 - BCL11A; 1561 (laplace), 169 (linear) and 692 (rbf) for RAD18 - BCL11A; 582 (laplace), 1144 (linear) and 1047 (rbf) for RAD50 - BCL11A; 1120 (laplace), 752 (linear) and 645 (rbf) for RAD51AP1 - BCL11A; 1024 (laplace), 199 (linear) and 899 (rbf) for RAD51C - BCL11A; and 1037 (laplace), 917 (linear) and 867 (rbf) for RAD54B - BCL11A. BCL11B was found to be down regulated w.r.t RAD-50/51/51AP1/54B/54L. These are reflected in rankings of 1198 (linear) and 903 (rbf) for RAD50 - BCL11B; 449 (linear) and 971 (rbf) for RAD51 - BCL11B; 1247 (laplace), 908 (linear) and 1671 (rbf) for RAD51AP1 - BCL11B; 1193 (laplace), 1192 (linear) and 832 (rbf) for RAD54B - BCL11B and 1421 (laplace) and 1385 (linear) for RAD54L - BCL11B.
On the right side, w.r.t BCL2L12, RAD-18/50/51/51AP1/51C/54B/54L were found to be down regulated. These are found in the rankings of 779 (laplace), 652 (linear) and 1388 (rbf) for RAD18 - BCL2L12; 1668 (laplace), 2566 (linear) and 1703 (rbf) for RAD50 - BCL2L12; 1164 (laplace), 365 (linear), 1213 (rbf) for RAD51 - BCL2L12; 306 (laplace), 57 (linear) and 28 (rbf) for RAD51AP1 - BCL2L12; 495 (laplace), 1191 (linear) and 429 (rbf) for RAD51C - BCL2L12; 678 (laplace), 432 (linear) and 787 (rbf) for RAD54B - BCL2L12; and 901 (laplace), 1128 (linear) and 263 (rbf) for RAD54L - BCL2L12; w.r.t BCL6B, RAD-18/51/51AP1/51C/54B/54L were found to be down regulated. These are reflected in rankings of 1113 (laplace), 640 (linear) and 482 (rbf) for RAD18 - BCL6B; 287 (laplace), 681 (linear) and 497 (rbf) for RAD51 - BCL6B; 1607 (laplace), 1638 (linear) and 916 (rbf) for RAD51AP1 - BCL6B; 43 (laplace), 871 (linear) and 999 (rbf) for RAD51C - BCL6B; 1212 (laplace), 1392 (linear) and 1170 (rbf) for RAD54B - BCL6B; and 1009 (linear) and 785 (rbf) for RAD54L - BCL6B; w.r.t BCL7A, RAD-18/51/51AP1/51C/54B/54L were found to be down regulated. These are reflected in rankings of 1514 (laplace), 1515 (linear), 783 (rbf) for RAD18 - BCL7A; 879 (laplace), 274 (linear) and 639 (rbf) for RAD51 - BCL7A; 412 (laplace), 416 (linear) and 4 (rbf) for RAD51AP1 - BCL7A; 215 (laplace), 394 (linear) and 461 (rbf) for RAD51C - BCL7A; 809 (laplace), 1407 (linear) and 213 (rbf) for RAD54B - BCL7A and 435 (laplace), 783 (linear) and 1499 (rbf) for RAD54L - BCL7A. w.r.t BCL9, RAD-18/50/51/51AP1/51C/54B/54L were found to be down regulated. These are reflected in the rankings of 656 (laplace), 1194 (linear) and 482 (rbf) for RAD18 - BCL9; 1441 (linear) and 1098 (rbf) for RAD50 - BCL9; 622 (laplace), 929 (linear), 860 (rbf) for RAD51 - BCL9; 331 (laplace), 61 (linear) and 102 (rbf) for RAD51AP1 - BCL9; 1113 (laplace), 417 (linear) and 1154 (rbf) for RAD51C - BCL9; 1045 (laplace), 53 (linear) and 650 (rbf) for RAD54B - BCL9 and 636 (laplace), 602 (linear) and 934 (rbf) for RAD54L - BCL9. w.r.t BCL11A, RAD-1/18/50/51/51AP1/51C/54B/54L were found to be down regulated. These are reflected in 1430 (laplace), 1475 (linear) and 1584 (rbf) for RAD1 - BCL11A; 465 (laplace) and 164 (linear) for RAD18 - BCL11A; 875 (linear) and 1226 (rbf) for RAD50 - BCL11A; 659 (laplace), 388 (linear) and 496 (rbf) for RAD51AP1 - BCL11A; 363 (laplace), 1673 (linear) and 97 (rbf) for RAD51C - BCL11A; 581 (laplace) and 799 (rbf) for RAD54B - BCL11A; and 846 (laplace) and 209 (rbf) for RAD54L - BCL11A; w.r.t BCL11B, RAD-1/50/51/51AP1/51C/54B/54L were found to be down regulated. These are reflected in rankings of 230 (linear) and 1373 (rbf) RAD1 - BCL11B; 919 (laplace) and 860 (linear) for RAD50 - BCL11B; 1095 (laplace) and 1238 (linear) RAD51 - BCL11B; 196 (laplace) and 987 (rbf) for RAD51AP1 - BCL11B; 1122 (laplace) and 1161 (rbf) for RAD51C - BCL11Bl; 363 (laplace) and 1561 (rbf) for RAD54B - BCL11B; 579 (laplace), 2543 (linear) and 159 (rbf) for RAD54L - BCL11B.
Table 9 shows the derived influences which can be represented graphically, with the following influences - • RAD w.r.t BCL with RAD-18/50/51/51AP1/51C/54B/54L < − BCL-2L12; RAD-18/51/51AP1/51C/54B/54L < − BCL-6B; RAD-18/51/51AP1/51C/54B/54L < − BCL-7A; RAD-18/50/51/51AP1/51C/54B/54L < − BCL-9; RAD-1/18/50/51/51AP1/51C/54B/54L < − BCL-11A; RAD-1/50/51/51AP1/51C/54B/54L < − BCL-11B; and • BCL w.r.t RAD with RAD-1/18/50/51/51C/54B/54L − > BCL-2L12; RAD-1/18/50/51/51AP1/51C/54B/54L − > BCL-6B; RAD-1/18/50/51/54L − > BCL-7A; RAD-18/51/51C/54L − > BCL-9; RAD-1/18/50/51/51AP1/51C/54B − > BCL-11A; and RAD-50/51/51AP1/54B/54L − > BCL-11B.

3.1.5. RAD - EXOSC Cross Family Analysis

Marin-Vicente et al. [12] show that RRP6/EXOSC10 is required for the repair of DNA double-strand breaks by homologous recombination. The authors results suggest that ribonucleolytic activity of RRP6/EXOSC10 is required for the recruitment of RAD51 to DSBs. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated in vitro by the strong knockdown of RAD51, a prospective therapeutic target for cancer cells (Shtam et al. [13]). These findings point to the synergy between EXOSC and RAD family. In CRC cells treated with ETC-1922159, they were down regulated and the search engine allocated low numerical rankings for combinations, thus pointing to possible synergistic down regulation. Table 10 shows the rankings of the EXOSC and RAD family w.r.t to each other. On the left half of the table is the rankings of EXOSC w.r.t RAD family. EXOSC2 was found to be down regulated w.r.t RAD-1/18/50/51/51AP1/51C/54B/54L. These are reflected in rankings of 1033 (laplace), 1311 (linear) and 1207 (rbf) for EXOSC2 - RAD1; 1210 (laplace) and 995 (linear) for EXOSC2 - RAD18; 1124 (laplace), 698 (linear) and 629 (rbf) for EXOSC2 - RAD50; 1754 (laplace), 191 (linear)and 633 (rbf) and for EXOSC2 - RAD51; 198 (laplace) and 1462 (linear) for EXOSC2 - RAD51AP1; 87 (laplace), 463 (linear) and 1130 (rbf) for EXOSC2 - RAD51C; 351 (laplace), 135 (linear) and 142 (rbf) for EXOSC2 - RAD54B; and 1131 (laplace), 1652 (linear) and 320 (rbf) for EXOSC2 - RAD54L. EXOSC3 was found to be down regulated w.r.t RAD-1/18/51/51AP1/54L. These are reflected in rankings of 1677 (linear) and 549 (rbf) for EXOSC3 - RAD1; 1676 (laplace) and 184 (rbf) for EXOSC3 - RAD18; 894 (laplace) and 1066 (linear) for EXOSC3 - RAD51; 1037 (linear) and 804 (rbf) for EXOSC3 - RAD51AP1, and 469 (linear) and 736 (rbf) for EXOSC3 - RAD54L. EXOSC5 was found to be down regulated w.r.t RAD-1/18/50/51/51AP1/51C/54B/54L. These are reflected in rankings of 568 (laplace), 1169 (linear) and 1699 (rbf) for EXOSC5 - RAD1; 219 (linear) and 1652 (rbf) for EXOSC5 - RAD18; 447 (laplace), 195 (linear) and 475 (rbf) for EXOSC5 - RAD50; 431 (linear) and 1121 (rbf) for EXOSC5 - RAD51; 1290 (laplace), 487 (linear) and 430 (rbf) for EXOSC5 - RAD51AP1; 1284 (laplace) and 1264 (linear) for EXOSC5 - RAD51C; 940 (laplace), 812 (linear) and 1036 (rbf) for EXOSC5 - RAD54B; and 408 (laplace) and 1407 (rbf) for EXOSC5 - RAD54L; EXOSC6 was found to be down regulated w.r.t RAD-18/51/54L. These were reflected in rankings of 1637 (laplace), 1599 (linear) and 2254 (rbf) for EXOSC6 - RAD18; 1056 (laplace), 1482 (linear) and 1007 (rbf) for EXOSC6 - RAD51; and 987 (laplace) and 1642 (rbf) for EXOSC6 - RAD54L; EXOSC7 was found to be down regulated w.r.t RAD-1/18/51C/54B/54L. These are reflected in rankings of 1735 (linear) and 1210 (rbf) for EXOSC7 - RAD1; 490 (laplace), 1688 (linear) and 1331 (rbf) for EXOSC7 - RAD18; 1113 (laplace), 1623 (linear) and 530 (rbf) for EXOSC7 - RAD51C; 1612 (linear) and 1191 (rbf) for EXOSC7 - RAD54B; and 1550 (laplace), 1754 (linear) and 1728 (rbf) for EXOSC7 - RAD54L; EXOSC8 was found to be down regulated w.r.t RAD-18/51/51AP1/54B/54L. These are reflected in 805 (laplace) and 1564 (rbf) for EXOSC8 - RAD18; 404 (laplace) and 1630 (linear) for EXOSC8 - RAD51; 1567 (linear) and 1701 (rbf) for EXOSC8 - RAD51AP1; 1562 (laplace) and 1736 (rbf) for EXOSC8 - RAD54B; and 1248 (laplace), 622 (linear) and 239 (rbf) for EXOSC8 - RAD54L; EXOSC9 was found to be down regulated w.r.t RAD-1/18/50/51/51C/54B/54L. These are reflected in rankings of 175 (linear) and 1648 (rbf) for EXOSC9 - RAD1; 1533 (laplace), 774 (linear) and 1180 (rbf) for EXOSC9 - RAD18; 545 (laplace), 183 (linear) and 467 (rbf) for EXOSC9 - RAD50; 866 (laplace), 106 (linear) and 99 (rbf) for EXOSC9 - RAD51; 110 (laplace), 742 (linear) and 200 (rbf) for EXOSC9 - RAD51C; 179 (laplace), 178 (linear) and 84 (rbf) for EXOSC9 - RAD54B and 1113 (laplace) and 22 (rbf) for EXOSC9 - RAD54L;
On the right half of the table is the rankings of RAD family w.r.t EXOSC. RAD-18/51/51C/54B/54L was found to be down regulated w.r.t EXOSC2. These are reflected in rankings of 1115 (laplace), 979 (linear) and 654(rbf) for EXOSC2 - RAD18; 795 (laplace), 1332 (linear) and 441(rbf) for EXOSC2 - RAD51; 636 (laplace), 564 (linear) and 152(rbf) for EXOSC2 - RAD51C; 278 (laplace), 132 (linear) and 282(rbf) for EXOSC2 - RAD54B and 125 (laplace), 888 (linear) and 545(rbf) for EXOSC2 - RAD54L. RAD-18/50/51/51AP1/51C/54B/54L was found to be down regulated w.r.t EXOSC3. These are reflected in rankings of 1468 (linear) and 767 (rbf) for EXOSC3 - RAD18; 1062 (laplace) and 596 (linear) for EXOSC3 - RAD50; 727 (laplace), 583 (linear) and 963 (rbf) for EXOSC3 - RAD51; 100 (laplace), 49 (linear) and 219 (rbf) for EXOSC3 - RAD51AP1; 663 (laplace), 869 (linear) and 887 (rbf) for EXOSC3 - RAD51C; 384 (laplace), 277 (linear) and 310 (rbf) for EXOSC3 - RAD54B and 546 (laplace), 1117 (linear) and 808 (rbf) for EXOSC3 - RAD54L; RAD-1/18/51/51AP1/51C/54B/54L was found to be down regulated w.r.t EXOSC5. These are reflected in rankings of 1716 (linear) and 1718 (rbf) for EXOSC5 - RAD1; 1026 (laplace), 550 (linear) and 253 (rbf) for EXOSC5 - RAD18; 260 (laplace), 1095 (linear) and 137 (rbf) for EXOSC5 - RAD51; 1555 (laplace) and 976 (rbf) for EXOSC5 - RAD51AP1; 233 (laplace), 1003 (linear) and 359 (rbf) for EXOSC5 - RAD51C; 834 (laplace), 1825 (linear) and 335 (rbf) for EXOSC5 - RAD54B; and 248 (laplace), 197 (linear) and 39 (rbf) for EXOSC5 - RAD54L. RAD-1/18/50/51AP1/51C/54L was found to be down regulated w.r.t EXOSC6. These are reflected in rankings of 142 (linear) and 639(rbf) for EXOSC6 - RAD1; 1118 (laplace), 1313 (linear) and 1549(rbf) for EXOSC6 - RAD18; 1722 (linear) and 575(rbf) for EXOSC6 - RAD50; 149 (laplace) and 1060 (linear) for EXOSC6 - RAD51AP1; 500 (laplace) and 1628 (linear) for EXOSC6 - RAD51C; and 885 (laplace), 271 (linear) and 1224(rbf) for EXOSC6 - RAD54L; RAD-18/51/51AP1/51C/54B/54L was found to be down regulated w.r.t EXOSC7. These were reflected in rankings of 441 (laplace), 385 (linear) and 1542(rbf) for EXOSC7 - RAD18; 376 (laplace), 1180 (linear) and 550(rbf) for EXOSC7 - RAD51; 35 (laplace), 97 (linear) and 786(rbf) for EXOSC7 - RAD51AP1; 854 (laplace), 671 (linear) and 1459(rbf) for EXOSC7 - RAD51C; 458 (laplace), 260 (linear) and 646(rbf) for EXOSC7 - RAD54B; and 464 (laplace), 528 (linear) and 790(rbf) for EXOSC7 - RAD54L; RAD-1/18/51/51AP1/51C/54B/54L was found to be down regulated w.r.t EXOSC8. These were reflected in rankings of 151 (linear) and 1563 (rbf) for EXOSC8 - RAD1; 764 (laplace), 523 (linear) and 29 (rbf) for EXOSC8 - RAD18; 98 (laplace), 1161 (linear) and 902 (rbf) for EXOSC8 - RAD51; 408 (laplace) and 541 (rbf) for EXOSC8 - RAD51AP1; 906 (laplace), 738 (linear) and 1052 (rbf) for EXOSC8 - RAD51C; 23 (laplace), 1578 (linear) and 130 (rbf) for EXOSC8 - RAD54B; and 651 (laplace), 1384 (linear) and 1047 (rbf) for EXOSC8 - RAD54L; RAD-1/18/50/51/51AP1/51C/54B/54L was found to be down regulated w.r.t EXOSC9. These were reflected in rankings of 1335 (laplace) and 978 (rbf) for EXOSC9 - RAD1; 54 (linear) and 540 (rbf) for EXOSC9 - RAD18; 211 (laplace) and 1377 (rbf) for EXOSC9 - RAD50; 807 (laplace), 74 (linear) and 429 (rbf) for EXOSC9 - RAD51; 103 (linear), 1210 (rbf) for EXOSC9 - RAD51AP1; 399 (laplace), 844 (linear) and 69 (rbf) for EXOSC9 - RAD51C; 466 (linear), 1286 (rbf) for EXOSC9 - RAD54B; and 536 (laplace), 724 (linear) and 414 (rbf) for EXOSC9 - RAD54L;
Table 11 shows the derived influences which can be represented graphically, with the following influences - • RAD w.r.t EXOSC with EXOSC-2 − > RAD-18/51/51C/54B/54L; EXOSC-3 − > RAD-18/50/51/51AP1/51C/54B/54L; EXOSC-5 − > RAD-1/18/51/51AP1/51C/54B/54L; EXOSC-6 − > RAD-1/18/50/51AP1/51C/54L; EXOSC-7 − > RAD-18/51/51AP1/51C/54B/54L; EXOSC-8 − > RAD-1/18/51/51AP1/51C/54B/54L; EXOSC-9 − > RAD-1/18/50/51/51AP1/51C/54B/54L; and • EXOSC w.r.t RAD with EXOSC-2 < − RAD-1/18/50/51/51AP1/51C/54B/54L; EXOSC-3 < − RAD-1/18/51/51AP1/54L; EXOSC-5 < − RAD-1/18/50/51/51AP1/51C/54B/54L; EXOSC-6 < − RAD-18/51/54L; EXOSC-7 < − RAD-1/18/51C/54B/54L; EXOSC-8 < − RAD-18/51/51AP1/54B/54L; and EXOSC-9 < − RAD-1/18/50/51/51C/54B/54L.

3.1.6. XRCC - EXOSC cross family analysis

Not much is known about XRCC - EXOSC synergy, however both were found to be down regulated in CRC cells after treatment with ETC-1922159. The search engine also allocated rankings of low numerical values to several combinations thus indicating plausible synergistic down regulations. Table 12 shows the rankings of XRCC vs EXOSC family members.
On the left half of the table is the rankings of EXOSC w.r.t XRCC family. EXOSC2 was found to be down regulated w.r.t XRCC-1/2/6/6BP1. These are reflected in rankings of 277 (laplace), 176 (linear) and 423 (rbf) for EXOSC2 - XRCC1; 8 (laplace), 38 (linear) and 100 (rbf) for EXOSC2 - XRCC2; 1252 (laplace), 398 (linear) and 623 (rbf) for EXOSC2 - XRCC6; and 935 (laplace) and 905 (linear) for EXOSC2 - XRCC6BP1; EXOSC3 was found to be down regulated w.r.t XRCC-6BP1. These are reflected in rankings of 1523 (linear) and 1356 (rbf) for EXOSC3 - XRCC6BP1; EXOSC5 was found to be down regulated w.r.t XRCC-1/2/6/6BP1. These are reflected in rankings of 741 (laplace), 291 (linear) and 8 (rbf) for EXOSC5 - XRCC1; 1244 (laplace), 791 (linear) and 702 (rbf) for EXOSC5 - XRCC2; 65 (laplace), 1064 (linear) and 322 (rbf) for EXOSC5 - XRCC6; and 416 (laplace), 880 (linear) and 1434 (rbf) for EXOSC5 - XRCC6BP1. EXOSC6 was found to be down regulated w.r.t XRCC-1/2. These are reflected in rankings of 985 (linear) and 1163 (rbf) for EXOSC6 - XRCC1 and 1512 (laplace), 648 (linear) and 1458 (rbf) for EXOSC6 - XRCC2; EXOSC7 was found to be down regulated w.r.t XRCC-1/6/6BP1. These are reflected in rankings of 1510 (linear) and 1603 (rbf) for EXOSC7 - XRCC1; 584 (laplace), 1523 (linear) and 1018 (rbf) for EXOSC7 - XRCC6; and 1419 (laplace) and 876 (rbf) for EXOSC7 - XRCC6BP1. EXOSC8 was found to be down regulated w.r.t XRCC-1. These are reflected in rankings of 1373 (laplace) and 1515 (linear) for EXOSC8 - XRCC1; EXOSC9 was found to be down regulated w.r.t XRCC-1/2/6/6BP1. These are reflected in rankings of 44 (laplace), 1214 (linear) and 1410 (rbf) for EXOSC9 - XRCC1; 496 (laplace), 672 (linear) and 840 (rbf) for EXOSC9 - XRCC2; 1121 (laplace), 151 (linear) and 689 (rbf) for EXOSC9 - XRCC6 and 362 (laplace), 463 (linear) and 1741 (rbf) for EXOSC9 - XRCC6BP1.
On the right half of the table is the rankings of XRCC w.r.t EXOSC family. W.r.t EXOSC2, XRCC-2 was found to be down regulated. These are reflected in rankings of 166 (laplace), 417 (linear) and 56 (rbf) for EXOSC2 - XRCC2. W.r.t W.r.t EXOSC3, XRCC-2 was found to be down regulated. These are reflected in rankings of 166 (laplace), 417 (linear) and 56 (rbf) for EXOSC3 - XRCC2. W.r.t EXOSC5, XRCC-2 was found to be down regulated. These are reflected in rankings of 1559 (laplace) and 56 (rbf) for EXOSC5 - XRCC2. W.r.t EXOSC6, XRCC-1/2/6/6BP1 were found to be down regulated. These are reflected in rankings of 509 (laplace) and 1046(rbf) for EXOSC6 - XRCC1; 486 (laplace) and 1901(rbf) for EXOSC6 - XRCC2; 35 (linear) and 188(rbf) for EXOSC6 - XRCC6; 1295 (linear) and 366 (rbf) for EXOSC6 - XRCC6BP1. W.r.t EXOSC7, XRCC-6 was found to be down regulated. These are reflected in rankings of 1229 (linear) and 987(rbf) for EXOSC7 - XRCC1; 176 (laplace), 436 (linear) and 788 (rbf) for EXOSC7 - XRCC2; and 1074 (laplace), 242 (linear) and 288(rbf) for EXOSC7 - XRCC6. W.r.t EXOSC8, XRCC-2 was found to be down regulated. These are reflected in rankings of 13 (laplace) and 6 (rbf) for EXOSC8 - XRCC2. W.r.t EXOSC9, XRCC-2 was found to be down regulated. These are reflected in rankings of 655 (linear) and 1526 (rbf) for EXOSC9 - XRCC2 and 1206 (laplace) and 1626 (rbf) for EXOSC9 - XRCC6BP1;
Table 13 shows the derived influences which can be represented graphically, with the following influences - • XRCC w.r.t EXOSC with EXOSC-2 − > XRCC-2; EXOSC-3 − > XRCC-2; EXOSC-5 − > XRCC-2; EXOSC-6 − > XRCC-6; EXOSC-7 − > XRCC-1/2/6; EXOSC-8 − > XRCC-2; EXOSC-9 − > XRCC-2/6BP1; and • EXOSC w.r.t XRCC with EXOSC-2 < − XRCC-1/2/6/6BP1; EXOSC-3 < − XRCC-6/6BP1; EXOSC-5 < − XRCC-1/2/6/6BP1; EXOSC-6 < − XRCC-1/2; EXOSC-7 <- XRCC-1/6/6BP1; EXOSC-8 < − XRCC-1; and EXOSC-9 < − XRCC-1/2/6/6BP1.

3.1.7. RAD - FANC Cross Family Analysis

Fanconi Anemia (FA) is rare genetic disorder that happens mainly due to defects in proteins responsible for DNA repair via homologous recombination (Walden and Deans [14]). Cohn and D’Andrea [15] provides a review on the recent discoveries in the Fanconi Anemia and DNA double-strand break (DSB) repair pathways, which underscore the importance of regulated chromatin loading in the DNA damage response. Romick-Rosendale et al. [16] study the role Fanconi anemia pathway in squamous Cell Carcinoma. A review of the interplay between Fanconi anemia and homologous recombination pathways in genome integrity has been conducted by Michl et al. [17]. Liang et al. [18] observe the role of trimeric RAD51 and RAD51AP1-UAF1 complex in FANCD2. Taniguchi et al. [19] observe S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51. Zadorozhny et al. [20] show Fanconi anemia associated mutations destabilize RAD51 filaments and impair replication fork protection. Geng et al. [21] find RAD18-mediated ubiquitination of PCNA activates the Fanconi anemia DNA repair network. Rad18 E3 ubiquitin ligase activity mediates Fanconi anemia pathway activation and cell survival following DNA topoisomerase 1 inhibition as shown by Palle and Vaziri [22]. García-Luis and Machín [23] observe that Fanconi anaemia-like Mph1 helicase backs up RAD54 and RAD5 to circumvent replication stress-driven chromosome bridges. These findings suggest deep interactive role between the RAD and FA family. In colorectal cancer cell treated with ETC-1922159 these were found to both families were found to be down regulated. Our search engine alloted low laved numerical ranks to many of the 2nd order combinations between the RAD - FANC family. This signifies possible synergistic mechanism between the two in CRC cells. Table 14 shows the rankings of each, with respect to the other. On the left half is the rankings of RAD family w.r.t FANC family and vice versa on the right half.
On the left half, we find, RAD-18/51/51AP1/51C/54B/54L were found to be down regulated w.r.t FANCB. These are reflected in rankings of 10 (laplace), 2219 (linear) and 625 (rbf) for RAD18 - FANCB; 247 (laplace), 73 (linear) and 610 (rbf) for RAD51 - FANCB; 479 (laplace), 1667 (linear) and 663 (rbf) for RAD51AP1 - FANCB; 769 (laplace), 536 (linear) and 887 (rbf) for RAD51C - FANCB; 468 (laplace), 133 (linear) and 438 (rbf) for RAD54B - FANCB; and 583 (laplace), 2131 (linear) and 160 (rbf) for RAD54L - FANCB. RAD-18/51/51AP1/54B/54L were found to be down regulated w.r.t FANCD2. These are reflected in rankings of 1035 (laplace), 1271 (linear) and 405 (rbf) for RAD18 - FANCD2; 885 (laplace) and 1383 (rbf) for RAD51 - FANCD2; 1734 (laplace), 644 (linear) and 1291 (rbf) for RAD51AP1 - FANCD2; 275 (laplace), 2460 (linear) and 478 (rbf) for RAD54B - FANCD2; and 493 (laplace) and 203 (rbf) for RAD54L - FANCD2; RAD-1/18/50/51/51C/54B/54L were found to be down regulated w.r.t FANCD2OS. These are reflected in rankings of 693 (laplace) and 1146 (rbf) for RAD1 - FANCD2OS; 1472 (laplace), 526 (linear) and 239 (rbf) for RAD18 - FANCD2OS; 178 (laplace) and 1534 (linear) for RAD50 - FANCD2OS; 1080 (linear) and 1226 (rbf) for RAD51 - FANCD2OS; 1297 (laplace), 977 (linear) and 1237 (rbf) for RAD51C - FANCD2OS; 475 (laplace), 1367 (linear) for RAD54B - FANCD2OS; 1227 (linear) and 252 (rbf) for RAD54L - FANCD2OS; RAD-1/18/50/51/51AP1/51C/54B/54L were found to be down regulated w.r.t FANCF. These are reflected in rankings of 1582 (linear) and 285 (rbf) for RAD1 - FANCF; 770 (laplace), 1329 (linear) and 1445 (rbf) for RAD18 - FANCF; 1403 (laplace), 1684 (linear) and 803 (rbf) for RAD50 - FANCF; 209 (laplace), 1247 (linear) for RAD51 - FANCF; 1681 (laplace), 13 (linear) for RAD51AP1 - FANCF; 1493 (laplace) and 224 (linear) for RAD51C - FANCF; 401 (laplace) and 143 (linear) for RAD54B - FANCF; for 690 (laplace), 829 (linear) for RAD54L - FANCF; RAD-1/18/50/51/51AP1/51C/54B/54L were found to be down regulated w.r.t FANCG. These are reflected in rankings of 755 (laplace), 393 (linear) and 82 (rbf) for RAD18 - FANCG; 345 (laplace), 114 (linear) and 295 (rbf) for RAD51 - FANCG; 957 (laplace), 218 (linear) and 1360 (rbf) for RAD51C - FANCG; 17 (laplace), 182 (linear) and 423 (rbf) for RAD54B - FANCG; and 1058 (laplace), 701 (linear) and 581 (rbf) for RAD54L - FANCG. RAD-18/50/51/51C/54B/54L were found to be down regulated w.r.t FANCG. These are reflected in rankings of 1693 (laplace)and 436 (rbf) for RAD18 - FANCI; 1703 (laplace) and 1458 (rbf) for RAD50 - FANCI; 1038 (laplace), 1668 (linear) and 310 (rbf) for RAD51 - FANCI; 597 (laplace) and 165 (linear) for RAD51C - FANCI; 557 (laplace) and 84 (linear) for RAD54B - FANCI; and 468 (laplace), 606 (linear) for RAD54L - FANCI.
On the right half, we find, FANCB to be down regulated w.r.t RAD-1/50/51/51AP1/51C/54B/54L. These are reflected in rankings of 1499 (laplace), 656 (linear) and 340 (rbf) for RAD1 - FANCB; 133 (laplace), 234 (linear) and 73 (rbf) for RAD50 - FANCB; 378 (linear) and 8 (rbf) for RAD51 - FANCB; 89 (laplace), 562 (linear) and 2 (rbf) for RAD51AP1 - FANCB; 460 (laplace), 187 (linear) and 86 (rbf) for RAD51C - FANCB; 486 (laplace), 891 (linear) and 568 (rbf) for RAD54B - FANCB and 41 (laplace) and 692 (rbf) for RAD54L - FANCB; FANCD2 was found to be down regulated w.r.t RAD-1/50/51/51AP1/51C/54B/54L. These are reflected in rankings of 1451 (laplace), 1605 (linear) and 796 (rbf) for RAD1 - FANCD2; 403 (linear) and 1299 (rbf) for RAD18 - FANCD2; 646 (laplace), 357 (linear) and 769 (rbf) for RAD50 - FANCD2; 591 (laplace) and 85 (rbf) for RAD51 - FANCD2; 993 (laplace) and 603 (linear) for RAD51AP1 - FANCD2; 629 (laplace), 656 (linear) and 620 (rbf) for RAD51C - FANCD2; 227 (laplace), 230 (linear) and 131 (rbf) for RAD54B - FANCD2. FANCD2OS2 was found to be down regulated w.r.t RAD-1/18/5051C/54B. These are reflected in rankings of 1455 (laplace) and 1624 (rbf) for RAD1 - FANCD2OS; 851 (laplace), 1457 (linear) and 653 (rbf) for RAD18 - FANCD2OS; 1477 (linear) and 1372 (rbf) for RAD50 - FANCD2OS; 1729 (laplace) and 779 (linear) for RAD51C - FANCD2OS; 1241 (linear) and 1637 (rbf) for RAD54B - FANCD2OS; FANCF was found to be down regulated w.r.t RAD-1/18/50/51C/54B. These are reflected in rankings of 1063 (laplace) and 196 (rbf) for RAD18 - FANCF; 1419 (linear) and 1676 (rbf) for RAD50 - FANCF; 1222 (laplace) and 1060 (linear) for RAD51 - FANCF; and 716 (linear) and 1262 (rbf) for RAD54L - FANCF; FANCG was found to be down regulated w.r.t RAD-1/50/51/51AP1/51C/54B. These are reflected in rankings of 825 (linear) and 843 (rbf) for RAD1 - FANCG; 695 (laplace), 511 (linear) and 933 (rbf) for RAD50 - FANCG; 1 (linear) and 397 (rbf) for RAD51 - FANCG; 661 (laplace), 400 (linear) and 23 (rbf) for RAD51AP1 - FANCG; 450 (laplace) and 1122 (rbf) for RAD51C - FANCG; 140 (laplace), 194 (linear) and 64 (rbf) for RAD54B - FANCG; FANCI was found to be down regulated w.r.t RAD-1/18/50/51/51AP1/51C/54B/54L. These are reflected in 897 (linear) and 664 (rbf) for RAD1 - FANCI; 1601 (laplace), 1161 (linear) and 1668 (rbf) for RAD18 - FANCI; 1133 (laplace), 1211 (linear) and 1238 (rbf) for RAD50 - FANCI; 1612 (laplace) and 1187 (rbf) for RAD51 - FANCI; 1513 (laplace), 1211 (linear) and 65 (rbf) for RAD51AP1 - FANCI; 143 (laplace), 137 (linear) and 87 (rbf) for RAD51C - FANCI; 178 (laplace), 350 (linear) and 76 (rbf) for RAD54B - FANCI; 211 (laplace) and 1128 (rbf) for RAD54L - FANCI.
Table 14 shows the derived influences which can be represented graphically, with the following influences - • RAD w.r.t FANC with RAD-18/51/51AP1/51C/54B/54L < − FANCB; RAD-18/51/51AP1/54B/54L < − FANCD2; RAD-1/18/50/51/51C/54B/54L < − FANCD2OS; RAD-1/18/50/51/51AP1/51C/54B/54L < − FANCF; RAD-1/18/50/51/51AP1/51C/54B/54L < − FANCG; and RAD-18/50/51/51C/54B/54L < − FANCI, and • FANC w.r.t RAD with FANCB < − RAD-1/50/51/51AP1/51C/54B/54L; FANCD2 < − RAD-1/50/51/51AP1/51C/54B/54L; FANCD2OS < − RAD-1/18/5051C/54B; FANCF < − RAD-1/18/50/51C/54B; FANCG < − RAD-1/50/51/51AP1/51C/54B; FANCI < − RAD-1/18/50/51/51AP1/51C/54B/54L;

Conclusions

Presented here are a range of multiple synergistic DNA repair gene 2nd order combinations that were ranked via a search engine. Later, two way cross family analysis between components of these combinations were conducted. Via majority voting across the ranking methods, it was possible to find plausible unexplored synergistic combinations that might be prevalent in CRC cells after treatment with ETC-1922159 drug. The two-way cross family analysis also assists in deriving influences between components which serve as hypotheses for further tests. If found true, it paves way for biologists/oncologists to further investigate and understand the mechanism behind the synergy through wet experiments.

Source of Data

Data used in this research work was released in a publication in Madan et al. [24]. The ETC-1922159 was released in Singapore in July 2015 under the flagship of the Agency for Science, Technology and Research (A*STAR) and Duke-National University of Singapore Graduate Medical School (Duke-NUS).

Author Contributions

Concept, design, in silico implementation - SS. Analysis and interpretation of results - SS. Manuscript writing - SS. Manuscript revision - SS. Approval of manuscript - SS

Acknowledgments

Special thanks to Mrs. Rita Sinha and Mr. Prabhat Sinha for supporting the author financially, without which this work could not have been made possible.

Conflicts of Interest

There are no conflicts to declare.

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Table 1. 2nd order interaction ranking between RAD w.r.t XRCC family members.
Table 1. 2nd order interaction ranking between RAD w.r.t XRCC family members.
Ranking RAD family w.r.t XRCC family
Ranking of RAD family w.r.t XRCC1 Ranking of RAD family w.r.t XRCC2
laplace linear rbf laplace linear rbf
RAD1 - XRCC1 1922 1658 1771 XRCC2 - RAD1 1921 893 1774
RAD18 - XRCC1 1027 456 1355 XRCC2 - RAD18 1388 847 765
XRCC1 - RAD50 2459 2254 2082 XRCC2 - RAD50 1877 2185 2546
RAD51 - XRCC1 282 365 1003 XRCC2 - RAD51 1247 1033 629
RAD51AP1 - XRCC1 753 5 275 XRCC2 - RAD51AP1 302 247 42
RAD51C - XRCC1 337 111 968 XRCC2 - RAD51C 1079 674 323
RAD54B - XRCC1 175 224 782 XRCC2 - RAD54B 387 566 506
RAD54L - XRCC1 327 889 709 XRCC2 - RAD54L 976 918 847
Ranking of RAD family w.r.t XRCC6 Ranking of RAD family w.r.t XRCC6BP1
laplace linear rbf laplace linear rbf
XRCC6 - RAD1 1929 2029 2627 RAD1 - XRCC6BP1 1167 2417 308
RAD18 - XRCC6 541 25 1068 RAD18 - XRCC6BP1 656 1612 2271
XRCC6 - RAD50 2434 2043 2603 XRCC6BP1 - RAD50 1302 2263 328
RAD51 - XRCC6 608 425 900 RAD51 - XRCC6BP1 435 495 1275
RAD51AP1 - XRCC6 216 67 83 RAD51AP1 - XRCC6BP1 81 177 73
RAD51C - XRCC6 426 865 503 RAD51C - XRCC6BP1 645 1366 1414
RAD54B - XRCC6 3 610 112 RAD54B - XRCC6BP1 154 693 1398
RAD54L - XRCC6 85 252 432 RAD54L - XRCC6BP1 420 1060 2542
Table 2. 2nd order interaction ranking between XRCC w.r.t RAD family members.
Table 2. 2nd order interaction ranking between XRCC w.r.t RAD family members.
Ranking XRCC family w.r.t RAD family
Ranking of XRCC w.r.t RAD1 Ranking of XRCC w.r.t RAD18
laplace linear rbf laplace linear rbf
RAD1 - XRCC1 1751 1808 793 RAD18 - XRCC1 927 2669 200
XRCC2 - RAD1 62 498 1231 XRCC2 - RAD18 506 1844 1517
XRCC6 - RAD1 2736 2511 1284 RAD18 - XRCC6 279 2193 804
RAD1 - XRCC6BP1 764 2108 1325 RAD18 - XRCC6BP1 819 1954 1976
Ranking of XRCC w.r.t RAD50 Ranking of XRCC w.r.t RAD51
laplace linear rbf laplace linear rbf
XRCC1 - RAD50 2573 2374 2497 RAD51 - XRCC1 1673 1818 2611
XRCC2 - RAD50 53 244 147 XRCC2 - RAD51 472 2348 1973
XRCC6 - RAD50 2615 2568 2582 RAD51 - XRCC6 80 1244 2595
RAD50 - XRCC6BP1 1962 1375 1366 RAD51 - XRCC6BP1 792 951 1595
Ranking of XRCC w.r.t RAD51AP1 Ranking of XRCC w.r.t RAD51C
laplace linear rbf laplace linear rbf
XRCC1 - RAD51AP1 1802 2732 801 RAD51C - XRCC1 2282 1846 2026
XRCC2 - RAD51AP1 78 112 351 XRCC2 - RAD51C 1695 932 520
XRCC6 - RAD51AP1 2653 2439 347 RAD51C - XRCC6 2545 1848 1858
RAD51AP1 - XRCC6BP1 1790 936 974 RAD51C - XRCC6BP1 2325 1070 1844
Ranking of XRCC w.r.t RAD54B Ranking of XRCC w.r.t RAD54L
laplace linear rbf laplace linear rbf
XRCC1 - RAD54B 2475 2670 1824 RAD54L - XRCC1 1834 657 525
XRCC2 - RAD54B 1554 744 620 XRCC2 - RAD54L 2564 167 565
XRCC6 - RAD54B 2505 2709 2604 RAD54L - XRCC6 2597 496 1247
RAD54B - XRCC6BP1 1932 2504 2170 RAD54L - XRCC6BP1 1389 1227 1454
Table 3. 2nd order combinatorial hypotheses between RAD and XRCC.
Table 3. 2nd order combinatorial hypotheses between RAD and XRCC.
Unexplored combinatorial hypotheses
RAD w.r.t XRCC family
RAD-18/51/51AP1/51C/54B/54L XRCC1
RAD-18/51/51AP1/51C/54B/54L XRCC2
RAD-18/51/51AP1/51C/54B/54L XRCC6
RAD-1/18/50/51/51AP1/51C/54B/54L XRCC6BP1
XRCC w.r.t RAD family
RAD1 XRCC-2/6BP1
RAD18 XRCC-1/2/6
RAD50 XRCC-2/6BP1
RAD51 XRCC-6/6BP1
RAD51AP1 XRCC-2/6BP1
RAD51C XRCC-2
RAD54B XRCC-2
RAD54L XRCC-1/2/6/6BP1
Table 4. 2nd order interaction ranking between RAD family vs XRN2.
Table 4. 2nd order interaction ranking between RAD family vs XRN2.
Ranking XRN2 w.r.t RAD family
Ranking of RAD family w.r.t XRN2 Ranking of XRN2 w.r.t RAD family
laplace linear rbf laplace linear rbf
XRN2 - RAD51AP1 340 545 290 XRN2 - RAD51AP1 1905 1256 852
XRN2 - RAD51 387 560 605 XRN2 - RAD51 786 2647 1995
XRN2 - RAD54L 594 827 879 XRN2 - RAD54L 1541 1246 1819
XRN2 - RAD51C 639 1236 745 XRN2 - RAD51C 1037 1777 2228
XRN2 - RAD18 794 688 804 XRN2 - RAD18 904 2403 1801
XRN2 - RAD1 898 1955 2506 XRN2 - RAD1 255 122 2557
XRN2 - RAD54B 951 165 343 XRN2 - RAD54B 1818 2381 2603
XRN2 - RAD50 1330 2312 2295 XRN2 - RAD50 504 2100 1842
Table 5. 2nd order combinatorial hypotheses between RAD and XRN2.
Table 5. 2nd order combinatorial hypotheses between RAD and XRN2.
Unexplored combinatorial hypotheses
RAD w.r.t XRN2
XRN2 RAD-51AP1/51/54L/51C/18/54B
XRN2 w.r.t RAD
XRN2 RAD1
XRN2 RAD51AP1
XRN2 RAD54L
XRN2 RAD51C
Table 6. 2nd order interaction ranking between RAD family vs NKRF.
Table 6. 2nd order interaction ranking between RAD family vs NKRF.
Ranking NKRF w.r.t RAD family
Ranking of NFRK w.r.t RAD family Ranking of RAD family w.r.t NKRF
laplace linear rbf laplace linear rbf
RAD51AP1 - NKRF 1724 1642 649 RAD51AP1 - NKRF 157 553 2561
RAD51 - NKRF 982 1724 1352 RAD51 - NKRF 439 1441 1606
RAD54L - NKRF 1727 1387 1120 RAD54L - NKRF 117 1175 1415
RAD51C - NKRF 1568 472 1505 RAD51C - NKRF 418 2178 1653
RAD18 - NKRF 1508 615 405 RAD18 - NKRF 164 2306 1509
RAD1 - NKRF 2667 2222 1181 NKRF - RAD1 1391 1115 735
RAD54B - NKRF 1476 1189 1534 RAD54B - NKRF 207 1869 2244
RAD50 - NKRF 2003 2343 2511 NKRF - RAD50 1354 851 824
Table 7. 2nd order combinatorial hypotheses between RAD and XRN2.
Table 7. 2nd order combinatorial hypotheses between RAD and XRN2.
Unexplored combinatorial hypotheses
RAD w.r.t NKRF
RAD51AP1 NKRF
RAD51 NKRF
RAD54L NKRF
RAD51C NKRF
RAD18 NKRF
RAD1 NKRF
RAD54B NKRF
NKRF w.r.t RAD
RAD51AP1 NKRF
RAD51 NKRF
RAD54L NKRF
RAD51C NKRF
RAD18 NKRF
NKRF RAD1
NKRF RAD50
Table 8. 2nd order interaction ranking between RAD and BCL family members.
Table 8. 2nd order interaction ranking between RAD and BCL family members.
Ranking RAD family VS BCL family
Ranking of BCL2L12 w.r.t RAD family Ranking of RAD family w.r.t BCL2L12
laplace linear rbf laplace linear rbf
RAD1 - BCL2L12 1797 1530 1401 RAD1 - BCL2L12 1958 2120 1957
RAD18 - BCL2L12 675 2437 1312 RAD18 - BCL2L12 779 652 1388
RAD50 - BCL2L12 2080 1151 929 RAD50 - BCL2L12 1668 2566 1703
RAD51 - BCL2L12 1234 1334 2350 RAD51 - BCL2L12 1164 365 1213
RAD51AP1 - BCL2L12 2267 2500 2265 RAD51AP1 - BCL2L12 306 57 28
RAD51C - BCL2L12 1561 2384 1647 RAD51C - BCL2L12 495 1191 429
RAD54B - BCL2L12 1979 1329 1625 RAD54B - BCL2L12 678 432 787
RAD54L - BCL2L12 2446 821 210 RAD54L - BCL2L12 901 1128 263
Ranking of BCL6B w.r.t RAD family Ranking of RAD family w.r.t BCL6B
laplace linear rbf laplace linear rbf
RAD1 - BCL6B 194 481 102 RAD1 - BCL6B 2110 2151 2059
RAD18 - BCL6B 1790 176 929 RAD18 - BCL6B 1113 640 482
RAD50 - BCL6B 860 87 74 RAD50 - BCL6B 2164 2412 2581
RAD51 - BCL6B 2324 263 58 RAD51 - BCL6B 287 681 497
RAD51AP1 - BCL6B 723 428 579 RAD51AP1 - BCL6B 1607 1638 916
RAD51C - BCL6B 660 521 1609 RAD51C - BCL6B 43 871 999
RAD54B - BCL6B 708 596 647 RAD54B - BCL6B 1212 1392 1170
RAD54L - BCL6B 108 2684 1326 RAD54L - BCL6B 1867 1009 785
Ranking of BCL7A w.r.t RAD family Ranking of RAD family w.r.t BCL7A
laplace linear rbf laplace linear rbf
RAD1 - BCL7A 690 1791 1202 RAD1 - BCL7A 1989 2101 1804
RAD18 - BCL7A 385 2366 185 RAD18 - BCL7A 1514 1515 783
RAD50 - BCL7A 137 601 417 RAD50 - BCL7A 2123 1771 2085
RAD51 - BCL7A 514 1694 2361 RAD51 - BCL7A 879 274 639
RAD51AP1 - BCL7A 2440 2609 774 RAD51AP1 - BCL7A 412 416 4
RAD51C - BCL7A 2726 2448 983 RAD51C - BCL7A 215 394 461
RAD54B - BCL7A 2729 1830 2743 RAD54B - BCL7A 809 1407 213
RAD54L - BCL7A 1519 418 842 RAD54L - BCL7A 435 783 1499
Ranking of BCL9 w.r.t RAD family Ranking of RAD family w.r.t BCL9
laplace linear rbf laplace linear rbf
RAD1 - BCL9 1296 2418 1775 RAD1 - BCL9 1749 2528 1391
RAD18 - BCL9 461 1952 1453 RAD18 - BCL9 656 1194 482
RAD50 - BCL9 2338 2653 2559 RAD50 - BCL9 2220 1441 1098
RAD51 - BCL9 1748 1143 952 RAD51 - BCL9 622 929 860
RAD51AP1 - BCL9 1861 2280 786 RAD51AP1 - BCL9 331 61 102
RAD51C - BCL9 956 2741 376 RAD51C - BCL9 1113 417 1154
RAD54B - BCL9 2063 2375 1050 RAD54B - BCL9 1045 53 650
RAD54L - BCL9 1450 1096 400 RAD54L - BCL9 636 602 934
Ranking of BCL11A w.r.t RAD family Ranking of RAD family w.r.t BCL11A
laplace linear rbf laplace linear rbf
RAD1 - BCL11A 1069 507 1267 RAD1 - BCL11A 1430 1475 1584
RAD18 - BCL11A 1561 169 692 RAD18 - BCL11A 465 164 1952
RAD50 - BCL11A 582 1144 1047 RAD50 - BCL11A 2649 875 1226
RAD51 - BCL11A 1722 2073 339 RAD51 - BCL11A 255 2064 2461
RAD51AP1 - BCL11A 1120 752 645 RAD51AP1 - BCL11A 659 388 496
RAD51C - BCL11A 1024 199 899 RAD51C - BCL11A 363 1673 97
RAD54B - BCL11A 1037 917 867 RAD54B - BCL11A 581 2743 799
RAD54L - BCL11A 172 2193 2318 RAD54L - BCL11A 846 2733 209
Ranking of BCL11B w.r.t RAD family Ranking of RAD family w.r.t BCL11B
laplace linear rbf laplace linear rbf
RAD1 - BCL11B 2371 2360 43 RAD1 - BCL11B 2571 230 1373
RAD18 - BCL11B 1741 993 2677 RAD18 - BCL11B 1747 2028 14
RAD50 - BCL11B 2010 1198 903 RAD50 - BCL11B 919 860 2263
RAD51 - BCL11B 2067 449 971 RAD51 - BCL11B 1095 1238 2373
RAD51AP1 - BCL11B 1247 908 1671 RAD51AP1 - BCL11B 196 2646 987
RAD51C - BCL11B 1736 1234 2282 RAD51C - BCL11B 1122 1844 1161
RAD54B - BCL11B 1193 1192 832 RAD54B - BCL11B 363 2150 1561
RAD54L - BCL11B 1421 1385 1854 RAD54L - BCL11B 579 2543 159
Table 9. 2nd order combinatorial hypotheses between RAD and BCL members.
Table 9. 2nd order combinatorial hypotheses between RAD and BCL members.
Unexplored combinatorial hypotheses
RAD w.r.t BCL
RAD-18/50/51/51AP1/51C/54B/54L BCL-2L12
RAD-18/51/51AP1/51C/54B/54L BCL-6B
RAD-18/51/51AP1/51C/54B/54L BCL-7A
RAD-18/50/51/51AP1/51C/54B/54L - BCL-9
RAD-1/18/50/51/51AP1/51C/54B/54L BCL-11A
RAD-1/50/51/51AP1/51C/54B/54L BCL-11B
BCL w.r.t RAD
RAD-1/18/50/51/51C/54B/54L BCL-2L12
RAD-1/18/50/51/51AP1/51C/54B/54L BCL-6B
RAD-1/18/50/51/54L BCL-7A
RAD-18/51/51C/54L BCL-9
RAD-1/18/50/51/51AP1/51C/54B BCL-11A
RAD-50/51/51AP1/54B/54L BCL-11B
Table 10. 2nd order interaction ranking between RAD and EXOSC family members.
Table 10. 2nd order interaction ranking between RAD and EXOSC family members.
Ranking RAD family VS EXOSC family
Ranking of EXOSC2 w.r.t RAD family Ranking of RAD family w.r.t EXOSC2
laplace linear rbf laplace linear rbf
EXOSC2 - RAD1 1033 1311 1207 EXOSC2 - RAD1 2456 1368 2292
EXOSC2 - RAD18 1210 995 1906 EXOSC2 - RAD18 1115 979 654
EXOSC2 - RAD50 1124 698 629 EXOSC2 - RAD50 1647 2495 2375
EXOSC2 - RAD51 1754 191 633 EXOSC2 - RAD51 795 1332 441
EXOSC2 - RAD51AP1 198 1462 2718 EXOSC2 - RAD51AP1 2320 1316 2127
EXOSC2 - RAD51C 87 463 1130 EXOSC2 - RAD51C 636 564 152
EXOSC2 - RAD54B 351 135 142 EXOSC2 - RAD54B 278 132 282
EXOSC2 - RAD54L 1131 1652 320 EXOSC2 - RAD54L 125 888 545
Ranking of EXOSC3 w.r.t RAD family Ranking of RAD family w.r.t EXOSC3
laplace linear rbf laplace linear rbf
EXOSC3 - RAD1 2492 1677 549 EXOSC3 - RAD1 2200 1243 2711
EXOSC3 - RAD18 1676 2516 184 EXOSC3 - RAD18 2024 1468 767
EXOSC3 - RAD50 2368 1892 2204 EXOSC3 - RAD50 1062 596 2346
EXOSC3 - RAD51 894 1066 2463 EXOSC3 - RAD51 727 583 963
EXOSC3 - RAD51AP1 1884 1037 804 EXOSC3 - RAD51AP1 100 49 219
EXOSC3 - RAD51C 2499 2356 1248 EXOSC3 - RAD51C 663 869 887
EXOSC3 - RAD54B 2183 2518 2360 EXOSC3 - RAD54B 384 277 310
EXOSC3 - RAD54L 1735 469 736 EXOSC3 - RAD54L 546 1117 808
Ranking of EXOSC5 w.r.t RAD family Ranking of RAD family w.r.t EXOSC5
laplace linear rbf laplace linear rbf
EXOSC5 - RAD1 568 1169 1699 EXOSC5 - RAD1 2405 1716 1718
EXOSC5 - RAD18 2481 219 1652 EXOSC5 - RAD18 1026 550 253
EXOSC5 - RAD50 447 195 475 EXOSC5 - RAD50 1596 1952 2271
EXOSC5 - RAD51 2548 431 1121 EXOSC5 - RAD51 260 1095 137
EXOSC5 - RAD51AP1 1290 487 430 EXOSC5 - RAD51AP1 1555 1860 976
EXOSC5 - RAD51C 1284 1264 1790 EXOSC5 - RAD51C 233 1003 359
EXOSC5 - RAD54B 940 812 1036 EXOSC5 - RAD54B 834 1825 335
EXOSC5 - RAD54L 408 2539 1407 EXOSC5 - RAD54L 248 197 39
Ranking of EXOSC6 w.r.t RAD family Ranking of RAD family w.r.t EXOSC6
laplace linear rbf laplace linear rbf
EXOSC6 - RAD1 2283 2490 1228 EXOSC6 - RAD1 2405 142 639
EXOSC6 - RAD18 1637 1599 2254 EXOSC6 - RAD18 1118 1313 1549
EXOSC6 - RAD50 2289 1969 1797 EXOSC6 - RAD50 2309 1722 575
EXOSC6 - RAD51 1056 1482 1007 EXOSC6 - RAD51 998 2297 2219
EXOSC6 - RAD51AP1 1854 2480 1827 EXOSC6 - RAD51AP1 149 1060 2731
EXOSC6 - RAD51C 1996 940 1842 EXOSC6 - RAD51C 500 1628 2409
EXOSC6 - RAD54B 2289 2312 2005 EXOSC6 - RAD54B 262 2703 2465
EXOSC6 - RAD54L 987 2240 1642 EXOSC6 - RAD54L 885 271 1224
Ranking of EXOSC7 w.r.t RAD family Ranking of RAD family w.r.t EXOSC7
laplace linear rbf laplace linear rbf
EXOSC7 - RAD1 2559 1735 1210 EXOSC7 - RAD1 2079 2308 1604
EXOSC7 - RAD18 490 1688 1331 EXOSC7 - RAD18 441 385 1542
EXOSC7 - RAD50 2661 1939 2021 EXOSC7 - RAD50 1840 406 2100
EXOSC7 - RAD51 842 1900 1876 EXOSC7 - RAD51 376 1180 550
EXOSC7 - RAD51AP1 2446 349 2374 EXOSC7 - RAD51AP1 35 97 786
EXOSC7 - RAD51C 1113 1623 530 EXOSC7 - RAD51C 854 671 1459
EXOSC7 - RAD54B 2431 1612 1191 EXOSC7 - RAD54B 458 260 646
EXOSC7 - RAD54L 1550 1754 1728 EXOSC7 - RAD54L 464 528 790
Ranking of EXOSC8 w.r.t RAD family Ranking of RAD family w.r.t EXOSC8
laplace linear rbf laplace linear rbf
EXOSC8 - RAD1 2380 2442 2630 EXOSC8 - RAD1 1928 151 1563
EXOSC8 - RAD18 805 2287 1564 EXOSC8 - RAD18 764 523 29
EXOSC8 - RAD50 1798 1830 1893 EXOSC8 - RAD50 2103 2649 1822
EXOSC8 - RAD51 404 1630 2092 EXOSC8 - RAD51 98 1161 902
EXOSC8 - RAD51AP1 1932 1567 1701 EXOSC8 - RAD51AP1 408 1824 541
EXOSC8 - RAD51C 2439 1576 2554 EXOSC8 - RAD51C 906 738 1052
EXOSC8 - RAD54B 1562 2542 1736 EXOSC8 - RAD54B 23 1578 130
EXOSC8 - RAD54L 1248 622 239 EXOSC8 - RAD54L 651 1384 1047
Ranking of EXOSC9 w.r.t RAD family Ranking of RAD family w.r.t EXOSC9
laplace linear rbf laplace linear rbf
EXOSC9 - RAD1 2240 175 1648 EXOSC9 - RAD1 1335 1799 978
EXOSC9 - RAD18 1533 774 1180 EXOSC9 - RAD18 2529 54 540
EXOSC9 - RAD50 545 183 467 EXOSC9 - RAD50 211 2217 1377
EXOSC9 - RAD51 866 106 99 EXOSC9 - RAD51 807 74 429
EXOSC9 - RAD51AP1 1570 1819 1807 EXOSC9 - RAD51AP1 2480 103 1210
EXOSC9 - RAD51C 110 742 200 EXOSC9 - RAD51C 399 844 69
EXOSC9 - RAD54B 179 178 84 EXOSC9 - RAD54B 2385 466 1286
EXOSC9 - RAD54L 1113 2436 22 EXOSC9 - RAD54L 536 724 414
Table 11. 2nd order combinatorial hypotheses between RAD and EXOSC members.
Table 11. 2nd order combinatorial hypotheses between RAD and EXOSC members.
Unexplored combinatorial hypotheses
RAD w.r.t EXOSC
EXOSC-2 RAD-18/51/51C/54B/54L
EXOSC-3 RAD-18/50/51/51AP1/51C/54B/54L
EXOSC-5 RAD-1/18/51/51AP1/51C/54B/54L
EXOSC-6 RAD-1/18/50/51AP1/51C/54L
EXOSC-7 RAD-18/51/51AP1/51C/54B/54L
EXOSC-8 RAD-1/18/51/51AP1/51C/54B/54L
EXOSC-9 RAD-1/18/50/51/51AP1/51C/54B/54L
EXOSC w.r.t RAD
EXOSC-2 RAD-1/18/50/51/51AP1/51C/54B/54L
EXOSC-3 RAD-1/18/51/51AP1/54L
EXOSC-5 RAD-1/18/50/51/51AP1/51C/54B/54L
EXOSC-6 RAD-18/51/54L
EXOSC-7 RAD-1/18/51C/54B/54L
EXOSC-8 RAD-18/51/51AP1/54B/54L
EXOSC-9 RAD-1/18/50/51/51C/54B/54L
Table 12. 2nd order interaction ranking between RAD and EXOSC family members.
Table 12. 2nd order interaction ranking between RAD and EXOSC family members.
Ranking XRCC family VS EXOSC family
Ranking of EXOSC2 w.r.t XRCC family Ranking of XRCC family w.r.t EXOSC2
laplace linear rbf laplace linear rbf
EXOSC2 - XRCC1 277 176 423 EXOSC2 - XRCC1 2708 2386 2634
EXOSC2 - XRCC2 8 38 100 EXOSC2 - XRCC2 166 417 56
EXOSC2 - XRCC6 1252 398 623 EXOSC2 - XRCC6 2678 2504 2576
EXOSC2 - XRCC6BP1 935 905 1755 EXOSC2 - XRCC6BP1 1740 1842 2177
Ranking of EXOSC3 w.r.t XRCC family Ranking of XRCC family w.r.t EXOSC3
laplace linear rbf laplace linear rbf
EXOSC3 - XRCC1 1551 2256 1974 EXOSC3 - XRCC1 2217 1418 2041
EXOSC3 - XRCC2 2462 2553 2329 EXOSC3 - XRCC2 125 15 194
EXOSC3 - XRCC6 1720 1716 2398 EXOSC3 - XRCC6 2742 2608 2193
EXOSC3 - XRCC6BP1 2506 1523 1356 EXOSC3 - XRCC6BP1 2561 2154 2406
Ranking of EXOSC5 w.r.t XRCC family Ranking of XRCC family w.r.t EXOSC5
laplace linear rbf laplace linear rbf
EXOSC5 - XRCC1 741 291 8 EXOSC5 - XRCC1 2578 2568 1910
EXOSC5 - XRCC2 1244 791 702 EXOSC5 - XRCC2 1559 1857 866
EXOSC5 - XRCC6 65 1064 322 EXOSC5 - XRCC6 2410 2465 2190
EXOSC5 - XRCC6BP1 416 880 1434 EXOSC5 - XRCC6BP1 1907 2029 1394
Ranking of EXOSC6 w.r.t XRCC family Ranking of XRCC family w.r.t EXOSC6
laplace linear rbf laplace linear rbf
EXOSC6 - XRCC1 1890 985 1163 EXOSC6 - XRCC1 509 2373 1046
EXOSC6 - XRCC2 1512 648 1458 EXOSC6 - XRCC2 486 2564 1901
EXOSC6 - XRCC6 2304 1719 2690 EXOSC6 - XRCC6 2576 35 188
EXOSC6 - XRCC6BP1 2428 492 2112 EXOSC6 - XRCC6BP1 1753 1295 366
Ranking of EXOSC7 w.r.t XRCC family Ranking of XRCC family w.r.t EXOSC7
laplace linear rbf laplace linear rbf
EXOSC7 - XRCC1 1907 1510 1603 EXOSC7 - XRCC1 1844 1229 987
EXOSC7 - XRCC2 1369 2555 2124 EXOSC7 - XRCC2 176 436 788
EXOSC7 - XRCC6 584 1523 1018 EXOSC7 - XRCC6 1074 242 288
EXOSC7 - XRCC6BP1 1419 1944 876 EXOSC7 - XRCC6BP1 2144 1577 2038
Ranking of EXOSC8 w.r.t XRCC family Ranking of XRCC family w.r.t EXOSC8
laplace linear rbf laplace linear rbf
EXOSC8 - XRCC1 1373 1515 2103 EXOSC8 - XRCC1 1769 2151 1435
EXOSC8 - XRCC2 1086 2309 2435 EXOSC8 - XRCC2 13 1932 6
EXOSC8 - XRCC6 1820 2542 2693 EXOSC8 - XRCC6 1869 1233 2625
EXOSC8 - XRCC6BP1 2112 1994 2699 EXOSC8 - XRCC6BP1 2305 2461 2319
Ranking of EXOSC9 w.r.t XRCC family Ranking of XRCC family w.r.t EXOSC9
laplace linear rbf laplace linear rbf
EXOSC9 - XRCC1 44 1214 1410 EXOSC9 - XRCC1 1804 2696 1629
EXOSC9 - XRCC2 496 672 840 EXOSC9 - XRCC2 1793 655 1526
EXOSC9 - XRCC6 1121 151 689 EXOSC9 - XRCC6 1882 2188 2404
EXOSC9 - XRCC6BP1 362 463 1741 EXOSC9 - XRCC6BP1 1206 1776 1626
Table 13. 2nd order combinatorial hypotheses between XRCC and EXOSC members.
Table 13. 2nd order combinatorial hypotheses between XRCC and EXOSC members.
Unexplored combinatorial hypotheses
XRCC w.r.t EXOSC
EXOSC-2 XRCC-2
EXOSC-3 XRCC-2
EXOSC-5 XRCC-2
EXOSC-6 XRCC-6
EXOSC-7 XRCC-1/2/6
EXOSC-8 XRCC-2
EXOSC-9 XRCC-2/6BP1
EXOSC w.r.t XRCC
EXOSC-2 XRCC-1/2/6/6BP1
EXOSC-3 XRCC-6/6BP1
EXOSC-5 XRCC-1/2/6/6BP1
EXOSC-6 XRCC-1/2
EXOSC-7 XRCC-1/6/6BP1
EXOSC-8 XRCC-1
EXOSC-9 XRCC-1/2/6/6BP1
Table 14. 2nd order combinatorial hypotheses between RAD and FANC members.
Table 14. 2nd order combinatorial hypotheses between RAD and FANC members.
Ranking RAD family VS FANC family
Ranking of RAD family w.r.t FANCB Ranking of FANCB w.r.t RAD family
laplace linear rbf laplace linear rbf
RAD1 - FANCB 2431 400 2553 RAD1 - FANCB 1499 656 340
RAD18 - FANCB 10 2219 625 RAD18 - FANCB 2708 383 2298
RAD50 - FANCB 2419 915 2556 RAD50 - FANCB 133 234 73
RAD51 - FANCB 247 73 610 RAD51 - FANCB 2444 378 8
RAD51AP1 - FANCB 479 1667 663 RAD51AP1 - FANCB 89 562 2
RAD51C - FANCB 769 536 887 RAD51C - FANCB 460 187 86
RAD54B - FANCB 468 133 438 RAD54B - FANCB 486 891 568
RAD54L - FANCB 583 2131 160 RAD54L - FANCB 41 2675 692
Ranking of RAD family w.r.t FANCD2 Ranking of FANCD2 w.r.t RAD family
laplace linear rbf laplace linear rbf
RAD1 - FANCD2 1935 332 2102 RAD1 - FANCD2 1451 1605 796
RAD18 - FANCD2 1035 1271 405 RAD18 - FANCD2 2356 403 1299
RAD50 - FANCD2 2109 436 2038 RAD50 - FANCD2 646 357 769
RAD51 - FANCD2 885 1995 1383 RAD51 - FANCD2 591 1938 85
RAD51AP1 - FANCD2 1734 644 1291 RAD51AP1 - FANCD2 993 603 2684
RAD51C - FANCD2 54 2399 2566 RAD51C - FANCD2 629 656 620
RAD54B - FANCD2 275 2460 478 RAD54B - FANCD2 227 230 131
RAD54L - FANCD2 493 2530 203 RAD54L - FANCD2 2457 1369 1816
Ranking of RAD family w.r.t FANCD2OS Ranking of FANCD2OS w.r.t RAD family
laplace linear rbf laplace linear rbf
RAD1 - FANCD2OS 693 1926 1146 RAD1 - FANCD2OS 1455 2445 1624
RAD18 - FANCD2OS 1472 526 239 RAD18 - FANCD2OS 851 1457 653
RAD50 - FANCD2OS 178 1534 2141 RAD50 - FANCD2OS 1763 1477 1372
RAD51 - FANCD2OS 2061 1080 1226 RAD51 - FANCD2OS 2007 2336 1739
RAD51AP1 - FANCD2OS 637 2050 2660 RAD51AP1 - FANCD2OS 2209 2376 1722
RAD51C - FANCD2OS 1297 977 1237 RAD51C - FANCD2OS 1729 779 2596
RAD54B - FANCD2OS 475 1367 2571 RAD54B - FANCD2OS 2032 1241 1637
RAD54L - FANCD2OS 2557 1227 252 RAD54L - FANCD2OS 1671 1830 1839
Ranking of RAD family w.r.t FANCF Ranking of FANCF w.r.t RAD family
laplace linear rbf laplace linear rbf
RAD1 - FANCF 1817 1582 285 RAD1 - FANCF 529 2198 1997
RAD18 - FANCF 770 1329 1445 RAD18 - FANCF 1063 2186 196
RAD50 - FANCF 1403 1684 803 RAD50 - FANCF 2205 1419 1676
RAD51 - FANCF 209 1247 2221 RAD51 - FANCF 1222 1060 2251
RAD51AP1 - FANCF 1681 13 2619 RAD51AP1 - FANCF 1963 2372 107
RAD51C - FANCF 1493 224 2051 RAD51C - FANCF 2062 1904 2386
RAD54B - FANCF 401 143 2359 RAD54B - FANCF 1903 1936 2026
RAD54L - FANCF 690 829 2120 RAD54L - FANCF 2529 716 1262
Ranking of RAD family w.r.t FANCG Ranking of FANCG w.r.t RAD family
laplace linear rbf laplace linear rbf
RAD1 - FANCG 2013 2215 2328 RAD1 - FANCG 1938 825 843
RAD18 - FANCG 755 393 82 RAD18 - FANCG 2352 878 2574
RAD50 - FANCG 2652 2408 2663 RAD50 - FANCG 695 511 933
RAD51 - FANCG 345 114 295 RAD51 - FANCG 2163 1 397
RAD51AP1 - FANCG 1743 749 1984 RAD51AP1 - FANCG 661 400 23
RAD51C - FANCG 957 218 1360 RAD51C - FANCG 450 2319 1122
RAD54B - FANCG 17 182 423 RAD54B - FANCG 140 194 64
RAD54L - FANCG 1058 701 581 RAD54L - FANCG 2167 1968 2344
Ranking of RAD family w.r.t FANCI Ranking of FANCI w.r.t RAD family
laplace linear rbf laplace linear rbf
RAD1 - FANCI 1919 2263 2286 RAD1 - FANCI 2496 897 664
RAD18 - FANCI 1693 2466 436 RAD18 - FANCI 1601 1161 1668
RAD50 - FANCI 1703 2074 1458 RAD50 - FANCI 1133 1211 1238
RAD51 - FANCI 1038 1668 310 RAD51 - FANCI 1612 2724 1187
RAD51AP1 - FANCI 2496 2517 383 RAD51AP1 - FANCI 1513 1211 65
RAD51C - FANCI 597 165 2447 RAD51C - FANCI 143 137 87
RAD54B - FANCI 557 84 2055 RAD54B - FANCI 178 350 76
RAD54L - FANCI 468 606 2461 RAD54L - FANCI 211 2304 1128
Table 15. 2nd order combinatorial hypotheses between RAD and FANC family.
Table 15. 2nd order combinatorial hypotheses between RAD and FANC family.
Unexplored combinatorial hypotheses
RAD w.r.t FANC
RAD-18/51/51AP1/51C/54B/54L FANCB
RAD-18/51/51AP1/54B/54L FANCD2
RAD-1/18/50/51/51C/54B/54L FANCD2OS
RAD-1/18/50/51/51AP1/51C/54B/54L FANCF
RAD-1/18/50/51/51AP1/51C/54B/54L FANCG
RAD-18/50/51/51C/54B/54L FANCI
FANC w.r.t RAD
FANCB RAD-1/50/51/51AP1/51C/54B/54L
FANCD2 RAD-1/50/51/51AP1/51C/54B/54L
FANCD2OS RAD-1/18/5051C/54B
FANCF RAD-1/18/50/51C/54B
FANCG RAD-1/50/51/51AP1/51C/54B
FANCI RAD-1/18/50/51/51AP1/51C/54B/54L
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