FAM35A associates with REV7 and modulates DNA damage responses of normal and BRCA1-defective cells.
FAM35A associates with REV7 and modulates DNA damage responses of normal and BRCA1-defective cells.
复制标题
DOI：
10.15252/embj.201899543
复制
发表时间：
2018-06-15
期刊：
影响因子：
--
通讯作者：
Wood RD
中科院分区：
文献类型：
--
作者：
Tomida J;Takata KI;Bhetawal S;Person MD;Chao HP;Tang DG;Wood RD
为了利用肿瘤的脆弱性，迫切需要识别基因组维护中的相关缺陷。一个尚未解决的问题是REV 7与53 BP 1和RIF 1复合物调节DNA双链断裂修复的机制，以及其对同源重组和非同源末端连接之间修复途径选择的影响。我们在人类细胞中搜索了REV 7相关因子，发现FAM 35 A是一种以前未研究过的蛋白质，具有非结构化的N-末端区域和C-末端区域，含有三个类似于单链DNA结合蛋白RPA的OB-折叠结构域，作为REV 7/RIF 1/53 BP 1的新型相互作用物。FAM 35 A重新定位于受损的细胞核中，其敲低导致对DNA损伤剂的敏感性。然而，在BRCA 1突变细胞系中，FAM 35 A的缺失增加了对喜树碱的耐药性，这表明FAM 35 A参与了DNA末端的加工，以实现更有效的DNA修复。我们发现FAM 35 A在一种广泛使用的BRCA 1突变癌细胞系（HCC 1937）中缺失，该细胞系对PARP抑制剂具有异常耐药性。FAM 35 A改变的调查显示，该基因在前列腺癌中的改变频率最高（高达13%），在转移性病例中的表达显著降低，揭示了FAM 35 A作为治疗相关癌症标志物的前景。
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.