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

EMBO J. 2018 Sep 14;37(18):e100158. doi: 10.15252/embj.2018100158. Epub 2018 Aug 28.


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.

Keywords: DNA double‐strand break; DNA repair pathway choice; REV7; non‐homologous end‐joining.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • DNA Breaks, Double-Stranded*
  • DNA End-Joining Repair*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • G2 Phase / genetics
  • HEK293 Cells
  • Humans
  • Mad2 Proteins / genetics
  • Mad2 Proteins / metabolism*
  • S Phase / genetics
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism
  • Tumor Suppressor p53-Binding Protein 1 / genetics
  • Tumor Suppressor p53-Binding Protein 1 / metabolism


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • MAD2L2 protein, human
  • Mad2 Proteins
  • Rif1 protein, human
  • SHLD2 protein, human
  • TP53BP1 protein, human
  • Telomere-Binding Proteins
  • Tumor Suppressor p53-Binding Protein 1