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
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.
