Zelceski, Anabel; Francica, Paola; Lingg, Lea; Mutlu, Merve; Stok, Colin; Liptay, Martin; Alexander, John; Baxter, Joseph S; Brough, Rachel; Gulati, Aditi; Haider, Syed; Raghunandan, Maya; Song, Feifei; Sridhar, Sandhya; Forment, Josep V; O'Connor, Mark J; Davies, Barry R; van Vugt, Marcel A T M; Krastev, Dragomir B; Pettitt, Stephen J; ... (2023). MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells. Cell reports, 42(5), p. 112484. Cell Press 10.1016/j.celrep.2023.112484
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The PSMC3IP-MND1 heterodimer promotes meiotic D loop formation before DNA strand exchange. In genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, depletion of PSMC3IP or MND1 causes sensitivity to poly (ADP-Ribose) polymerase inhibitors (PARPi) used in cancer treatment. PSMC3IP or MND1 depletion also causes ionizing radiation sensitivity. These effects are independent of PSMC3IP/MND1's role in mitotic alternative lengthening of telomeres. PSMC3IP- or MND1-depleted cells accumulate toxic RAD51 foci in response to DNA damage, show impaired homology-directed DNA repair, and become PARPi sensitive, even in cells lacking both BRCA1 and TP53BP1. Epistasis between PSMC3IP-MND1 and BRCA1/BRCA2 defects suggest that abrogated D loop formation is the cause of PARPi sensitivity. Wild-type PSMC3IP reverses PARPi sensitivity, whereas a PSMC3IP p.Glu201del mutant associated with D loop defects and ovarian dysgenesis does not. These observations suggest that meiotic proteins such as MND1 and PSMC3IP have a greater role in mitotic DNA repair.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) 05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology 05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) |
Graduate School: |
Graduate School for Cellular and Biomedical Sciences (GCB) |
UniBE Contributor: |
Francica, Paola, Lingg, Lea, Mutlu, Merve, Liptay, Martin, Rottenberg, Sven |
Subjects: |
600 Technology > 610 Medicine & health 600 Technology > 630 Agriculture |
ISSN: |
2211-1247 |
Publisher: |
Cell Press |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
11 May 2023 10:21 |
Last Modified: |
29 Nov 2023 09:39 |
Publisher DOI: |
10.1016/j.celrep.2023.112484 |
PubMed ID: |
37163373 |
Uncontrolled Keywords: |
CP: Molecular biology DNA repair MND1 PARP inhibitor PSMC3IP PSMC3IP and PARPi sensitivity |
BORIS DOI: |
10.48350/182446 |
URI: |
https://boris.unibe.ch/id/eprint/182446 |
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