RHINO directs MMEJ to repair DNA breaks in mitosis Journal Article


Authors: Brambati, A.; Sacco, O.; Porcella, S.; Heyza, J.; Kareh, M.; Schmidt, J. C.; Sfeir, A.
Article Title: RHINO directs MMEJ to repair DNA breaks in mitosis
Abstract: 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.
Keywords: double-strand breaks; damage; reveals; mechanism; complex; homologous-recombination; pol-theta; polymerase theta; fork breakage; live-cell
Journal Title: Science
Volume: 381
Issue: 6658
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science  
Date Published: 2023-08-11
Start Page: 653
End Page: 660
Language: English
Copyright Statement: PDF request sent to DDS (TC 2023-10-12)
ACCESSION: WOS:001054584400027
DOI: 10.1126/science.adh3694
PROVIDER: wos
PMCID: PMC10561558
PUBMED: 37440612
Notes: Article -- SI -- Source: Wos
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  1. Agnel Sfeir
    16 Sfeir
  2. Olivia Sacco
    4 Sacco