MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells.
Date
2023-05-30Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
CP: Molecular biology
DNA repair
MND1
PARP inhibitor
PSMC3IP
PSMC3IP and PARPi sensitivity
Poly(ADP-ribose) Polymerase Inhibitors
Antineoplastic Agents
DNA Repair
DNA Damage
BRCA1 Protein
Recombinational DNA Repair
Cell Line, Tumor
Research team
Gene Function
Language
eng
Date accepted
2023-04-24
License start date
2023-05-30
Citation
Cell Reports, 2023, 42 (5), pp. 112484 -
Publisher
CELL PRESS