| Title: |
MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells. |
| Authors: |
Zelceski, A; Francica, P; Lingg, L; Mutlu, M; Stok, C; Liptay, M; Alexander, J; Baxter, JS; Brough, R; Gulati, A; Haider, S; Raghunandan, M; Song, F; Sridhar, S; Forment, JV; O'Connor, MJ; Davies, BR; van Vugt, MATM; Krastev, DB; Pettitt, SJ; Tutt, ANJ; Rottenberg, S; Lord, CJ |
| Contributors: |
Zelceski, Anabel; Haider, Syed; Song, Feifei; Krastev, Dragomir; Pettitt, Stephen; Tutt, Andrew; Lord, Christopher |
| Publisher Information: |
CELL PRESS |
| Publication Year: |
2023 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Subject Terms: |
CP: Molecular biology; DNA repair; MND1; PARP inhibitor; PSMC3IP; PSMC3IP and PARPi sensitivity; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents; DNA Damage; BRCA1 Protein; Recombinational DNA Repair; Cell Line; Tumor |
| Subject Geographic: |
United States |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
Print-Electronic; application/pdf |
| Language: |
English |
| ISSN: |
2211-1247 |
| Relation: |
ARTN 112484; S2211-1247(23)00495-3; Cell Reports, 2023, 42 (5), pp. 112484 -; https://repository.icr.ac.uk/handle/internal/5918 |
| DOI: |
10.1016/j.celrep.2023.112484 |
| Availability: |
https://doi.org/10.1016/j.celrep.2023.112484; https://repository.icr.ac.uk/handle/internal/5918 |
| Rights: |
http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.67D7554C |
| Database: |
BASE |