MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

Anabel Zelceski; Paola Francica; Lea Lingg; Merve Mutlu; Colin Stok; Martin Liptay; John Alexander; Joseph S Baxter; Rachel Brough; Aditi Gulati; Syed Haider; Maya Raghunandan; Feifei Song; Sandhya Sridhar; Josep V Forment; Mark J O'Connor; Barry R Davies; Marcel A T M van Vugt; Dragomir B Krastev; Stephen J Pettitt; Andrew N J Tutt; Sven Rottenberg; Christopher J Lord

doi:10.1016/j.celrep.2023.112484

MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

Cell Rep. 2023 May 30;42(5):112484. doi: 10.1016/j.celrep.2023.112484. Epub 2023 May 9.

Authors

Anabel Zelceski¹, Paola Francica², Lea Lingg², Merve Mutlu³, Colin Stok⁴, Martin Liptay³, John Alexander⁵, Joseph S Baxter¹, Rachel Brough¹, Aditi Gulati⁵, Syed Haider⁵, Maya Raghunandan⁵, Feifei Song¹, Sandhya Sridhar¹, Josep V Forment⁶, Mark J O'Connor⁶, Barry R Davies⁶, Marcel A T M van Vugt⁶, Dragomir B Krastev¹, Stephen J Pettitt⁷, Andrew N J Tutt⁸, Sven Rottenberg⁹, Christopher J Lord¹⁰

Affiliations

¹ The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK; Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
² Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; Departement of Biomedical Research (DBMR), Cancer Therapy Resistance Cluster, University of Bern, 3012 Bern, Switzerland.
³ Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
⁴ Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands.
⁵ Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
⁶ Oncology R&D, AstraZeneca, Cambridge, UK.
⁷ The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK; Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. Electronic address: Stephen.pettitt@icr.ac.uk.
⁸ Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. Electronic address: Andrew.tutt@icr.ac.uk.
⁹ Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; Departement of Biomedical Research (DBMR), Cancer Therapy Resistance Cluster, University of Bern, 3012 Bern, Switzerland; Division of Molecular Pathology, The Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Bern Center for Precision Medicine, University of Bern, 3012 Bern, Switzerland. Electronic address: sven.rottenberg@vetsuisse.unibe.ch.
¹⁰ The CRUK Gene Function Laboratory, The Institute of Cancer Research, London SW3 6JB, UK; Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. Electronic address: Chris.lord@icr.ac.uk.

PMID: 37163373
DOI: 10.1016/j.celrep.2023.112484

Abstract

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.

Keywords: CP: Molecular biology; DNA repair; MND1; PARP inhibitor; PSMC3IP; PSMC3IP and PARPi sensitivity.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents*
BRCA1 Protein / genetics
Cell Line, Tumor
DNA Damage
DNA Repair
Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology
Recombinational DNA Repair

Substances

Poly(ADP-ribose) Polymerase Inhibitors
Antineoplastic Agents
BRCA1 Protein