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bioRxiv · 10.1101/287375

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

Tomida, J.·Takata, K.-i.·Bhetawal, S.·Person, M. D.·Chao, H.-P.·Tang, D. G.·Wood, R. D.
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Abstract

In order to exploit the specific vulnerabilities of tumors, it is urgent to identify the basis of associated defects in genome maintenance. One unsolved problem is the mechanism of inhibition of processing of DNA double-strand break repair by REV7 and its influence on DNA repair pathways. We searched for REV7-associated proteins in human cells and found FAM35A, a protein of previously unknown function. By analyzing the FAM35A sequence we discovered that FAM35A has an unstructured N-terminal region and a C-terminal region harboring three OB-fold domains similar to single-stranded binding protein RPA. Knockdown of FAM35A caused sensitivity to DNA damaging agents, and FAM35A re-localized in damaged cell nuclei. 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. Moreover, 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 in cancer revealed that the gene is altered at the highest frequency in prostate cancers (up to 13%) and significantly less expressed in metastatic cases. The results reveal a new DNA repair factor with promise as a therapeutically relevant cancer marker.

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Tomida, J., Takata, K.-i., Bhetawal, S., Person, M. D., Chao, H.-P., Tang, D. G., Wood, R. D.. 2018-03-22. FAM35A associates with REV7 and modulates DNA damage responses of normal and BRCA1-defective cells. https://doi.org/10.1101/287375

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