MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

Zelceski, A.; Francica, P.; Lingg, L.; Mutlu, M.; Stok, C.; Liptay, M.; Alexander, J.; Baxter, J. S.; Brough, R.; Gulati, A.; Haider, S.; Raghunandan, M.; Song, F.; Sridhar, S.; Forment, J. V.; OConnor, M. J.; Davies, B. R.; van Vugt, M. A. T. M.; Krastev, D. B.; Pettitt, S. J.; Tutt, A. N. J.; Rottenberg, S.; Lord, C. J.

doi:10.1101/2022.08.24.505108

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bioRxiv · 10.1101/2022.08.24.505108

MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

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Abstract

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.

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Zelceski, A., Francica, P., Lingg, L., Mutlu, M., Stok, C., Liptay, M., Alexander, J., Baxter, J. S., Brough, R., Gulati, A., Haider, S., Raghunandan, M., Song, F., Sridhar, S., Forment, J. V., OConnor, M. J., Davies, B. R., van Vugt, M. A. T. M., Krastev, D. B., Pettitt, S. J., Tutt, A. N. J., Rottenberg, S., Lord, C. J.. 2022-08-26. MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells. https://doi.org/10.1101/2022.08.24.505108

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