Cell Reports (May 2023)
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
Affiliations
- Anabel Zelceski
- 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
- Paola Francica
- 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
- Lea Lingg
- 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
- Merve Mutlu
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
- Colin Stok
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands
- Martin Liptay
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
- John Alexander
- Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
- Joseph S. Baxter
- 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
- Rachel Brough
- 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
- Aditi Gulati
- Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
- Syed Haider
- Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
- Maya Raghunandan
- Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK
- Feifei Song
- 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
- Sandhya Sridhar
- 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
- Josep V. Forment
- Oncology R&D, AstraZeneca, Cambridge, UK
- Mark J. O’Connor
- Oncology R&D, AstraZeneca, Cambridge, UK
- Barry R. Davies
- Oncology R&D, AstraZeneca, Cambridge, UK
- Marcel A.T.M. van Vugt
- Oncology R&D, AstraZeneca, Cambridge, UK
- Dragomir B. Krastev
- 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
- Stephen J. Pettitt
- 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; Corresponding author
- Andrew N.J. Tutt
- Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK; Corresponding author
- Sven Rottenberg
- 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; Corresponding author
- Christopher J. Lord
- 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; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 5
p. 112484
Abstract
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.
