Functional Radiogenetic Profiling Implicates ERCC6L2 in Non-homologous End Joining.

Abstract

Using genome-wide radiogenetic profiling, we functionally dissect vulnerabilities of cancer cells to ionizing radiation (IR). We identify ERCC6L2 as a major determinant of IR response, together with classical DNA damage response genes and members of the recently identified shieldin and CTC1-STN1-TEN1 (CST) complexes. We show that ERCC6L2 contributes to non-homologous end joining (NHEJ), and it may exert this function through interactions with SFPQ. In addition to causing radiosensitivity, ERCC6L2 loss restores DNA end resection and partially rescues homologous recombination (HR) in BRCA1-deficient cells. As a consequence, ERCC6L2 deficiency confers resistance to poly (ADP-ribose) polymerase (PARP) inhibition in tumors deficient for both BRCA1 and p53. Moreover, we show that ERCC6L2 mutations are found in human tumors and correlate with a better overall survival in patients treated with radiotherapy (RT); this finding suggests that ERCC6L2 is a predictive biomarker of RT response.

• Authors: Paola Francica, Merve Mutlu, Vincent A Blomen, Catarina Oliveira, Zuzanna Nowicka, Anika Trenner, Nora M Gerhards, Peter Bouwman, Elmer Stickel, Maarten L Hekkelman, Lea Lingg, Ismar Klebic, Marieke van de Ven, Renske de Korte-Grimmerink, Denise Howald, Jos Jonkers, Alessandro A Sartori, Wojciech Fendler, J Ross Chapman, Thijn Brummelkamp, Sven Rottenberg
• Journal: Cell reports (Cell Rep) Vol. 32 Issue 8 Pg. 108068 (08 25 2020) ISSN: 2211-1247 [Electronic] United States
• PMID: 32846126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• DNA Helicases
• ERCC6L2 protein, human

Topics

• Animals
• DNA End-Joining Repair (radiation effects)
• DNA Helicases (metabolism)
• Humans
• Mice