FAM35A associates with REV7 and modulates DNAdamage responses of normal and BRCA1-defective cells

被引:80
作者
Tomida, Junya [1 ]
Takata, Kei-ichi [1 ]
Bhetawal, Sarita [1 ]
Person, Maria D. [2 ]
Chao, Hsueh-Ping [1 ]
Tang, Dean G. [3 ]
Wood, Richard D. [1 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Smithville, TX 78957 USA
[2] Univ Texas Austin, Prote Facil, Austin, TX 78712 USA
[3] Roswell Pk Canc Inst, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA
基金
美国国家卫生研究院;
关键词
camptothecin; cisplatin; DNA repair; olaparib; prostate cancer; REPLICATION PROTEIN-A; DNA-POLYMERASE-ZETA; REPAIR; BRCA1; MAD2L2; ACTIVATION; INHIBITOR; RESECTION; SUBTYPES; NETWORKS;
D O I
10.15252/embj.201899543
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:14
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