Version 1
: Received: 14 October 2024 / Approved: 14 October 2024 / Online: 15 October 2024 (10:13:10 CEST)
How to cite:
Lee, J.; Kim, E.; Kim, H.; Kim, Y.-J.; Kim, S. H. MEGF11 Activates RAD52‐Dependent ALT through the NELL2‐PAX7 Transcriptional Cascade during Malignant Transformation of MPNSTs. Preprints2024, 2024101142. https://doi.org/10.20944/preprints202410.1142.v1
Lee, J.; Kim, E.; Kim, H.; Kim, Y.-J.; Kim, S. H. MEGF11 Activates RAD52‐Dependent ALT through the NELL2‐PAX7 Transcriptional Cascade during Malignant Transformation of MPNSTs. Preprints 2024, 2024101142. https://doi.org/10.20944/preprints202410.1142.v1
Lee, J.; Kim, E.; Kim, H.; Kim, Y.-J.; Kim, S. H. MEGF11 Activates RAD52‐Dependent ALT through the NELL2‐PAX7 Transcriptional Cascade during Malignant Transformation of MPNSTs. Preprints2024, 2024101142. https://doi.org/10.20944/preprints202410.1142.v1
APA Style
Lee, J., Kim, E., Kim, H., Kim, Y. J., & Kim, S. H. (2024). MEGF11 Activates RAD52‐Dependent ALT through the NELL2‐PAX7 Transcriptional Cascade during Malignant Transformation of MPNSTs. Preprints. https://doi.org/10.20944/preprints202410.1142.v1
Chicago/Turabian Style
Lee, J., Young-Joon Kim and Seung Hyun Kim. 2024 "MEGF11 Activates RAD52‐Dependent ALT through the NELL2‐PAX7 Transcriptional Cascade during Malignant Transformation of MPNSTs" Preprints. https://doi.org/10.20944/preprints202410.1142.v1
Abstract
Backgroud
In eukaryotes with a double-stranded linear DNA genome, the loss of terminal DNA during replication is inevitable due to an end-replication problem and telomeres serve as a buffer against DNA loss. Cumulative telomere attrition leads to replicative senescence and the Hayflick limit. Thus, activation of the telomere maintenance mechanism (TMM) is a prerequisite for malignant transformation. We show that extracellular, but not intracellular, signals activate RAD52-dependent alternative lengthening of telomeres (ALT) during malignant transformation of malignant peripheral nerve sheath tumors (MPNSTs).
Methods
We compared neurofibroma (NF, benign) and MPNST occurring in the same patient with type-1 neurofibromatosis, where each NF-MPNST pair shares the same genetic background and differentiation lineage minimizing genetic bias and contrasts only changes related to malignant transformation.
Results
We found that the MEGF11 and the MEGF11-dependent ephrin signaling pathways (EFNA5-EPHPA6-PDZD9/PARD6B) activate the NELL2-PAX7 transcriptional cascade, which sequentially activates RAD52, the recombinase of RAD52-dependent ALT, resulting in telomere elongation, metastasis, and poor prognosis. In contrast, H2AFX, a DNA damage marker and intracellular signal, activates RAD51-dependent ALT to determine the MPNST grade.
Conclusions
We demonstrated the extracellular signals that activate RAD52-dependent ALT and distinguished the biological and clinical manifestations of RAD51 and RAD52-dependent ALT during malignant transformation of MPNSTs.
Keywords
telomere; MEGF11; ephrin; NELL2; PAX7; RAD52‐dependent ALT
Subject
Medicine and Pharmacology, Oncology and Oncogenics
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
