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MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells.
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.
Affiliation
  • Zelceski A; 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.
  • Francica P; 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.
  • Lingg L; 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.
  • Mutlu M; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
  • Stok C; Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713GZ Groningen, the Netherlands.
  • Liptay M; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
  • Alexander J; Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
  • Baxter JS; 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.
  • Brough R; 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.
  • Gulati A; Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
  • Haider S; Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
  • Raghunandan M; Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
  • Song F; 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.
  • Sridhar S; 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.
  • Forment JV; Oncology R&D, AstraZeneca, Cambridge, UK.
  • O'Connor MJ; Oncology R&D, AstraZeneca, Cambridge, UK.
  • Davies BR; Oncology R&D, AstraZeneca, Cambridge, UK.
  • van Vugt MATM; Oncology R&D, AstraZeneca, Cambridge, UK.
  • Krastev DB; 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.
  • Pettitt SJ; 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.
  • Tutt ANJ; Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. Electronic address: Andrew.tutt@icr.ac.uk.
  • Rottenberg S; 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,
  • Lord CJ; 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.
Cell Rep ; 42(5): 112484, 2023 05 30.
Article in En | MEDLINE | ID: mdl-37163373
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Poly(ADP-ribose) Polymerase Inhibitors / Antineoplastic Agents Type of study: Diagnostic_studies Language: En Journal: Cell Rep Year: 2023 Document type: Article Affiliation country:
Fulltext
Add to My VHL
Print
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PubMed Links
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Poly(ADP-ribose) Polymerase Inhibitors / Antineoplastic Agents Type of study: Diagnostic_studies Language: En Journal: Cell Rep Year: 2023 Document type: Article Affiliation country: