Abstract
To exploit vulnerabilities of tumors, it is urgent to identify associated defects in genome maintenance. One unsolved problem is the mechanism of regulation of DNA double‐strand break repair by REV7 in complex with 53BP1 and RIF1, and its influence on repair pathway choice between homologous recombination and non‐homologous end‐joining. We searched for REV7‐associated factors in human cells and found FAM35A, a previously unstudied protein with an unstructured N‐terminal region and a C‐terminal region harboring three OB‐fold domains similar to single‐stranded DNA‐binding protein RPA, as novel interactor of REV7/RIF1/53BP1. FAM35A re‐localized in damaged cell nuclei, and its knockdown caused sensitivity to DNA‐damaging agents. In a BRCA1‐mutant cell line, however, depletion of FAM35A increased resistance to camptothecin, suggesting that FAM35A participates in processing of DNA ends to allow more efficient DNA repair. We found FAM35A absent in one widely used BRCA1‐mutant cancer cell line (HCC1937) with anomalous resistance to PARP inhibitors. A survey of FAM35A alterations revealed that the gene is altered at the highest frequency in prostate cancers (up to 13%) and significantly less expressed in metastatic cases, revealing promise for FAM35A as a therapeutically relevant cancer marker.
Highlights
REV7 is a multifunctional protein encoded by the MAD2L2 gene in human cells
It was proposed that REV7, together with 53BP1 and RIF1, inhibits 50 DNA end resection to promote non-homologous end-joining at the expense of homologous recombination
FAM35A interacts with REV7, 53BP1, and RIF1 in vivo
Summary
REV7 is a multifunctional protein encoded by the MAD2L2 gene in human cells. REV7 acts as an interaction module in several cellular pathways. DNA repair proteins associating with FAM35A included REV7, RIF1, BLM, and TOP3A (Table 2), with relatively more RIF1 peptides and 53BP1 identified following MMC exposure (Table 3). The C-terminal portion of FAM35A is predicted to contain three OB-fold domains structurally homologous to those in the 70 kDa subunit (RPA1) of the single-stranded DNA-binding protein RPA (Figs 2A and EV1).
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