XRCC1 promotes replication restart, nascent fork degradation and mutagenic DNA repair in BRCA2-deficient cells.

Autor:	Eckelmann BJ; Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA., Bacolla A; Departments of Cancer Biology and Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Wang H; Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA., Ye Z; Departments of Cancer Biology and Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Guerrero EN; Gorgas Memorial Institute for Health Studies, Panama City, Panama., Jiang W; National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, 518036, China., El-Zein R; Department of Radiology, Houston Methodist Research Institute, Houston, TX 77030, USA., Hegde ML; Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA., Tomkinson AE; Departments of Internal Medicine and Molecular Genetics & Microbiology, and the University of New Mexico Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA., Tainer JA; Departments of Cancer Biology and Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., Mitra S; Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX 77030, USA.
Jazyk:	angličtina
Zdroj:	NAR cancer [NAR Cancer] 2020 Sep; Vol. 2 (3), pp. zcaa013. Date of Electronic Publication: 2020 Aug 01.
DOI:	10.1093/narcan/zcaa013
Abstrakt:	Homologous recombination/end joining (HR/HEJ)-deficient cancers with BRCA mutations utilize alternative DNA double-strand break repair pathways, particularly alternative non-homologous end joining or microhomology-mediated end joining (alt-EJ/MMEJ) during S and G2 cell cycle phases. Depletion of alt-EJ factors, including XRCC1, PARP1 and POLQ, is synthetically lethal with BRCA2 deficiency; yet, XRCC1 roles in HR-deficient cancers and replication stress are enigmatic. Here, we show that after replication stress, XRCC1 forms an active repair complex with POLQ and MRE11 that supports alt-EJ activity in vitro . BRCA2 limits XRCC1 recruitment and repair complex formation to suppress alt-EJ at stalled forks. Without BRCA2 fork protection, XRCC1 enables cells to complete DNA replication at the expense of increased genome instability by promoting MRE11-dependent fork resection and restart. High XRCC1 and MRE11 gene expression negatively impacts Kaplan-Meier survival curves and hazard ratios for HR-deficient breast cancer patients in The Cancer Genome Atlas. The additive effects of depleting both BRCA2 and XRCC1 indicate distinct pathways for replication restart. Our collective data show that XRCC1-mediated processing contributes to replication fork degradation, replication restart and chromosome aberrations in BRCA2-deficient cells, uncovering new roles of XRCC1 and microhomology-mediated repair mechanisms in HR-deficient cancers, with implications for chemotherapeutic strategies targeting POLQ and PARP activities. (© The Author(s) 2020. Published by Oxford University Press on behalf of NAR Cancer.)
Databáze:	MEDLINE
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