RHINO directs MMEJ to repair DNA breaks in mitosis

• 成果类型: Article
• 署名作者: Brambati, Alessandra; Sacco, Olivia; Porcella, Sarina; Heyza, Joshua; Kareh, Mike; Schmidt, Jens C.; Sfeir, Agnel
• 署名单位: Memorial Sloan Kettering Cancer Center; Michigan State University; Michigan State University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12091
• DOI: 10.1126/science.adh3694
• 发表日期: 2023-08-11
• 页码: 653-+
• 关键词: double-strand breaks; polymerase theta; homologous-recombination; pol-theta; fork breakage; live-cell; damage; mechanism; reveals; complex

摘要

Nonhomologous end-joining (NHEJ) and homologous recombination (HR) are the primary pathways for repairing DNA double-strand breaks (DSBs) during interphase, whereas microhomology-mediated end-joining (MMEJ) has been regarded as a backup mechanism. Through CRISPR-Cas9-based synthetic lethal screens in cancer cells, we identified subunits of the 9-1-1 complex (RAD9A-RAD1-HUS1) and its interacting partner, RHINO, as crucial MMEJ factors. We uncovered an unexpected function for RHINO in restricting MMEJ to mitosis. RHINO accumulates in M phase, undergoes Polo-like kinase 1 (PLK1) phosphorylation, and interacts with polymerase theta (Pol theta), enabling its recruitment to DSBs for subsequent repair. Additionally, we provide evidence that MMEJ activity in mitosis repairs persistent DSBs that originate in S phase. Our findings offer insights into the synthetic lethal relationship between the genes POLQ and BRCA1 and BRAC2 and the synergistic effect of Pol theta and poly(ADP-ribose) polymerase (PARP) inhibitors.