MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

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. P...

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Published in:Cell reports (Cambridge) Vol. 42; no. 5; p. 112484
Main Authors: 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., Tutt, Andrew N.J., Rottenberg, Sven, Lord, Christopher J.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 30.05.2023
Elsevier
Subjects:
CP: Molecular biology
DNA repair
MND1
PARP inhibitor
PSMC3IP
PSMC3IP and PARPi sensitivity
PSMC3IP
CP: Molecular biology
MND1
PSMC3IP and PARPi sensitivity
DNA repair
PARP inhibitor
ISSN:2211-1247, 2211-1247
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Summary: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. [Display omitted] •The PSMC3IP-MND1 heterodimer controls meiotic DNA recombination•PSMC3IP-MND1 controls mitotic recombination•PSMC3IP-MND1 loss causes PARPi sensitivity genes in mitotic cells•PSMC3IP-MND1 loss causes a D loop defect and toxic RAD51 Processes used by meiotic cells to recombine chromosomes are also often co-opted in mitotic DNA repair. Zelceski et al. show that the meiotic PSMC3IP-MND1 heterodimer plays a critical role in the response to DNA damage in mitotic cells, including the response to PARPi used in cancer treatment.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2023.112484