ASF1A promotes NHEJ over homologous recombination for DNA double-strand break (DSB) repair.
Major finding: ASF1A promotes NHEJ over homologous recombination for DNA double-strand break (DSB) repair.
Mechanism: ASF1A promotes histone ubiquitin ligase recruitment to DSBs to facilitate 53BP1 recruitment for NHEJ.
Impact: ASF1A is deleted in some tumors and may predict response to radiotherapy or DSB-inducing chemotherapy.
DNA double-strand breaks (DSB) can promote genomic instability and cancer when not repaired. DSB repair occurs predominantly through nonhomologous end joining (NHEJ), and ubiquitination of histones near DSB sites is involved in promoting NHEJ over homologous recombination (HR). Lee and colleagues elucidated a mechanism by which the histone chaperone ASF1A facilitates the recruitment of histone ubiquitin ligases to promote DSB repair by NHEJ. Depletion of ASF1A conferred sensitivity to ionizing radiation and bleomycin, which introduce DSBs that are generally repaired by NHEJ. ASF1A loss suppressed DSB repair by NHEJ, with a weak compensatory increase in repair by HR. ASF1A was required for recruitment of 53BP1, which promotes NHEJ over HR, and enhanced recruitment of the HR-suppressing BRCA1–RAP80 complex while inhibiting recruitment of the HR-promoting BRCA1–CtIP complex. ASF1A bound directly to mediator of DNA damage checkpoint protein 1 (MDC1), promoted the phosphorylation of MDC1 by activated ATM, and prolonged the localization and activation of ATM at DSBs to facilitate NHEJ. ASF1A was required for phosphorylated MDC1–mediated recruitment of the E3 ubiquitin ligases RNF8 and RNF168 to DSBs. RNF8/RNF168 promoted ubiquitination of histones H2A and H2AX and facilitated recruitment of 53BP1 and BRCA1–RAP80 to promote NHEJ. Thus, the decrease in RNF8/RNF168 recruitment in ASF1A-depleted cells explains the impairment of histone ubiquitination, 53BP1 recruitment, and NHEJ. The function of ASF1 is independent of its histone chaperone activity. Analysis of data from CBioportal revealed that ASF1A is deleted in a fraction of patients with cancer including 10%–15% of patients with diffuse large B-cell lymphoma and prostate adenocarcinoma. Altogether, these findings define a role for ASF1A in promoting DSB repair by NHEJ. Further, ASF1A depletion conferred sensitivity DSBs, and ASF1A was deleted in some tumors, suggesting the possibility for ASF1A loss as a biomarker for response to radiotherapy or DSB-inducing chemotherapy.
Lee KY, Im JS, Shibata E, Dutta A. ASF1a promotes non-homologous end joining repair by facilitating phosphorylation of MDC1 by ATM at double-strand breaks. Mol Cell 2017;68:61–75.e5.
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