SHLD2/FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice

Steven Findlay, John Heath, Vincent M. Luo, Abba Malina, Théo Morin, Yan Coulombe, Billel Djerir, Zhigang Li, Arash Samiei, Estelle Simo-Cheyou, Martin Karam, Halil Bagci, Dolev Rahat, Damien Grapton, Elise G. Lavoie, Christian Dove, Husam Khaled, Hellen Kuasne, Koren K. Mann, Kathleen Oros KleinCelia M. Greenwood, Yuval Tabach, Morag Park, Jean Francois Côté, Jean Yves Masson, Alexandre Maréchal, Alexandre Orthwein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

DNA double-strand breaks (DSBs) can be repaired by two major pathways: non-homologous end-joining (NHEJ) and homologous recombination (HR). DNA repair pathway choice is governed by the opposing activities of 53BP1, in complex with its effectors RIF1 and REV7, and BRCA1. However, it remains unknown how the 53BP1/RIF1/REV7 complex stimulates NHEJ and restricts HR to the S/G2 phases of the cell cycle. Using a mass spectrometry (MS)-based approach, we identify 11 high-confidence REV7 interactors and elucidate the role of SHLD2 (previously annotated as FAM35A and RINN2) as an effector of REV7 in the NHEJ pathway. FAM35A depletion impairs NHEJ-mediated DNA repair and compromises antibody diversification by class switch recombination (CSR) in B cells. FAM35A accumulates at DSBs in a 53BP1-, RIF1-, and REV7-dependent manner and antagonizes HR by limiting DNA end resection. In fact, FAM35A is part of a larger complex composed of REV7 and SHLD1 (previously annotated as C20orf196 and RINN3), which promotes NHEJ and limits HR. Together, these results establish SHLD2 as a novel effector of REV7 in controlling the decision-making process during DSB repair.

Original languageAmerican English
Article numbere100158
JournalEMBO Journal
Volume37
Issue number18
DOIs
StatePublished - 14 Sep 2018

Bibliographical note

Funding Information:
We are grateful to Amelie Fradet-Turcotte, Michael Witcher, Josie Ursini-Siegel, Chantal Autexier, and William Foulkes for critical reading of the manuscript; to Daniel Durocher, Anne-Claude Gingras, Jeremy Stark, Michael Witcher, and Roger Greenberg for plasmids and other reagents. We would like to specifically thank Roderick McInnes, Josie Ursini-Siegel, and Koren Mann for their constant support. JH, VL, and MK received a doctoral fellowship from the Cole Foundation. AM was supported by a post-doctoral fellowship from the Cole Foundation. ESC received a FRQS post-doctoral training scholarship. HB was supported by a doctoral training award from the FRQS (#33603). JFC is the recipient of the TRANSAT chair in Breast Cancer Research. JYM is a FRQS Chair in Genome Stability. AO is the Canada Research Chair (Tier 2) in Genome Stability and Hematological Malignancies. Work in the AO laboratory was supported by a CIHR Project Grant (#376245), a CRS Operating Grant (#21038), a Transition Grant from the Cole Foundation, and an internal Operating Fund from the Sir Mortimer B. Davis Foundation of the Jewish General Hospital. Work in the JFC laboratory was supported by a NSERC Discovery Grant (RGPIN-2016-04808). Work in the AM laboratory was supported by a NSERC Discovery Grant (#5026) and a CIHR Project Grant (#376288). “Life always offers you a second chance. It is called tomorrow!”. Work in the JYM laboratory was supported by a CIHR Foundation grant.

Funding Information:
We are grateful to Amelie Fradet-Turcotte, Michael Witcher, Josie Ursini-Siegel, Chantal Autexier, and William Foulkes for critical reading of the manuscript; to Daniel Durocher, Anne-Claude Gingras, Jeremy Stark, Michael Witcher, and Roger Greenberg for plasmids and other reagents. We would like to specifically thank Roderick McInnes, Josie Ursini-Siegel, and Koren Mann for their constant support. JH, VL, and MK received a doctoral fellowship from the Cole Foundation. AM was supported by a post-doctoral fellowship from the Cole Foundation. ESC received a FRQS post-doctoral training scholarship. HB was supported by a doctoral training award from the FRQS (#33603). JFC is the recipient of the TRANSAT chair in Breast Cancer Research. JYM is a FRQS Chair in Genome Stability. AO is the Canada Research Chair (Tier 2) in Genome Stability and Hematological Malignancies. Work in the AO laboratory was supported by a CIHR Project Grant (#376245), a CRS Operating Grant (#21038), a Transition Grant from the Cole Foundation, and an internal Operating Fund from the Sir Mortimer B. Davis Foundation of the Jewish General Hospital. Work in the JFC laboratory was supported by a NSERC Discovery Grant (RGPIN-2016-04808). Work in the AM laboratory was supported by a NSERC Discovery Grant (#5026) and a CIHR Project Grant (#376288). ?Life always offers you a second chance. It is called tomorrow!?. Work in the JYM laboratory was supported by a CIHR Foundation grant.

Publisher Copyright:
© 2018 The Authors. Published under the terms of the CC BY 4.0 license

Keywords

  • DNA double-strand break
  • DNA repair pathway choice
  • REV7
  • non-homologous end-joining

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