RHINO directs MMEJ to repair DNA breaks in mitosis

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 i...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2023-08, Vol.381 (6658), p.653-660
Main Authors: Brambati, Alessandra, Sacco, Olivia, Porcella, Sarina, Heyza, Joshua, Kareh, Mike, Schmidt, Jens C, Sfeir, Agnel
Format: Article
Language:English
Subjects:
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Chromosomes
Deoxyribonucleic acid
DNA
DNA Breaks, Double-Stranded
DNA damage
DNA End-Joining Repair
DNA repair
Exonucleases - genetics
Exonucleases - metabolism
Genomes
HEK293 Cells
Homologous recombination
Humans
Mitosis
Mitosis - genetics
Phosphorylation
Polo-like kinase 1
Poly(ADP-ribose) Polymerases - metabolism
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Summary: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 θ (Polθ), 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 and and and the synergistic effect of Polθ and poly(ADP-ribose) polymerase (PARP) inhibitors.
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.adh3694