MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

The PSMC3IP-MND1 heterodimer promotes RAD51 and DMC1-dependent D-loop formation during meiosis in yeast and mammalian organisms. For this purpose, it catalyzes the DNA strand exchange activities of the recombinases. Interestingly, in a panel of genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, we found that depletion of either PSMC3IP or MND1 caused sensitivity to clinical Poly (ADP-Ribose) Polymerase inhibitors (PARPi). A retroviral mutagenesis screen in mitotic cells also identified PSMC3IP and MND1 as genetic determinants of ionizing radiation sensitivity. The role PSMC3IP and MND1 play in preventing PARPi sensitivity in mitotic cells appears to be independent of a previously described role in alternative lengthening of telomeres (ALT). 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 . Although replication fork reversal is also affected, the epistatic relationship between PSMC3IP-MND1 and BRCA1/BRCA2 suggests that the abrogated D-loop formation is the major cause of PARPi sensitivity. This is corroborated by the fact that a PSMC3IP p.Glu201del D-loop formation mutant associated with ovarian dysgenesis fails to reverse PARPi sensitivity. These observations suggest that meiotic proteins such as MND1 and PSMC3IP could have a greater role in mitotic cells in determining the response to therapeutic DNA damage. ### Competing Interest Statement C.J.L. makes the following disclosures: receives and/or has received research funding from: AstraZeneca, Merck KGaA, Artios. Received consultancy, SAB membership or honoraria payments from: Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, Artios, Abingworth, Tesselate, Dark Blue Therapeutics. Has stock in: Tango, Ovibio, Enedra Tx., Hysplex, Tesselate. C.J.L. is also a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from their development and use as part of the ICR Rewards to Inventors scheme and also reports benefits from this scheme associated with patents for PARP inhibitors paid into CJL personal account and research accounts at the Institute of Cancer Research. A.N.J.T. reports personal honoraria from Pfizer, Vertex, Prime Oncology, Artios, MD Anderson, Medscape Education, EM Partners, GBCC conference, Cancer Panel, Research to Practise, honoraria to either the Institute of Cancer Research or Kings College research accounts from SABCS, VJ oncology, GE healthcare, Gilead, AZ ESMO symposium, IBCS conference, AstraZeneca Ad boards, honoraria and stock in InBioMotion, honoraria and financial support for research from AstraZeneca, Medivation, Myriad Genetics, Merck Serono. Travel expenses covered by AstraZeneca for any trial-related meetings or trial commitments abroad. A.N.J.T. reports benefits from ICR's Inventors Scheme associated with patents for PARP inhibitors in BRCA1/2 associated cancers, paid into research accounts at the Institute of Cancer Research and to A.N.J.T.'s personal account. JVF, MOC and BRD are full time employees and shareholders at AstraZeneca.