The repair of DNA double strand breaks (DSBs) that arise from external mutagenic agents and routine cellular processes is essential for life. DSBs are repaired by two major pathways, homologous recombination (HR) and classical nonhomologous end joining (C-NHEJ). DSB repair pathway choice is largely dictated at the step of 5′-3′ DNA end resection, which is promoted during S phase, in part by BRCA1. Opposing end resection is the 53BP1 protein, which recruits the ssDNA-binding REV7-Shieldin complex to favor C-NHEJ repair. We recently identified TRIP13 as a proresection factor that remodels REV7, causing its dissociation from the Shieldin subunit SHLD3. Here, we identify p31^comet, a negative regulator of MAD2 and the spindle assembly checkpoint, as an important mediator of the TRIP13-REV7 interaction. p31^comet binds to the REV7-Shieldin complex in cells, promotes REV7 inactivation, and causes PARP inhibitor resistance. p31^comet also participates in the extraction of REV7 from the chromatin. Furthermore, p31^comet can counteract REV7 function in translesion synthesis (TLS) by releasing it from REV3 in the Pol ζ complex. Finally, p31^comet, like TRIP13, is overexpressed in many cancers and this correlates with poor prognosis. Thus, we reveal a key player in the regulation of HR and TLS with significant clinical implications.

由外部诱变剂和常规细胞过程引起的DNA双链断裂（DSB）的修复对于生命至关重要。DSB通过两条主要途径修复，即同源重组（HR）和经典非同源末端连接（C-NHEJ）。DSB修复途径的选择主要取决于5'-3'DNA末端切除的步骤，该步骤在S期得到促进，部分是由BRCA1促进的。与末端切除相反的是53BP1蛋白，该蛋白募集结合ssDNA的REV7-Shieldin复合物以促进C-NHEJ修复。我们最近发现TRIP13是重塑REV7的前切除因子，导致REV7与Shieldin亚基SHLD3分离。在这里，我们确定p31^彗星，MAD2的负调节剂和主轴组件检查点是TRIP13-REV7相互作用的重要介体。31^彗星与细胞中的REV7-Shieldin复合物结合，促进REV7失活，并引起PARP抑制剂耐药。p31^彗星还参与从染色质中提取REV7。此外，p31^彗星可以通过在Polζ复合体中将REV7从REV3中释放出来来抵消REV7在跨病变合成（TLS）中的功能。最后，p31^彗星像TRIP13一样在许多癌症中过表达，这与预后不良有关。因此，我们揭示了具有重要临床意义的HR和TLS调节的关键参与者。