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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