SHLD2/FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice.
SHLD2/FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice.
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DOI：
10.15252/embj.2018100158
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发表时间：
2018-09-14
期刊：
影响因子：
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通讯作者：
Orthwein A
中科院分区：
文献类型：
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作者：
Findlay S;Heath J;Luo VM;Malina A;Morin T;Coulombe Y;Djerir B;Li Z;Samiei A;Simo-Cheyou E;Karam M;Bagci H;Rahat D;Grapton D;Lavoie EG;Dove C;Khaled H;Kuasne H;Mann KK;Klein KO;Greenwood CM;Tabach Y;Park M;Côté JF;Masson JY;Maréchal A;Orthwein A
DNA双链断裂（DSB）可以通过两种主要途径修复：非同源末端连接（NHEJ）和同源重组（HR）。DNA修复途径的选择由53 BP 1的相反活性控制，与其效应物RIF 1和REV 7以及BRCA 1复合。然而，53 BP 1/RIF 1/REV 7复合物如何刺激NHEJ并将HR限制在细胞周期的S/G2期仍然是未知的。使用基于质谱（MS）的方法，我们确定了11个高置信度的REV 7相互作用因子，并阐明了SHLD 2（先前注释为FAM 35 A和RINN 2）作为REV 7在NHEJ通路中的效应子的作用。FAM 35 A缺失损害NHEJ介导的DNA修复，并通过B细胞中的类别转换重组（CSR）损害抗体多样化。FAM 35 A以53 BP 1-、RIF 1-和REV 7-依赖性方式在DSB处积累，并通过限制DNA末端切除来拮抗HR。事实上，FAM 35 A是由REV 7和SHLD 1（之前注释为C20 orf 196和RINN 3）组成的更大复合体的一部分，该复合体促进NHEJ并限制HR。总之，这些结果确定SHLD 2是REV 7在控制决策过程中的新型效应子DSB修复过程。
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.