MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells
Date
2023-10-10ICR Author
Author
Lord C
Zelceski, A
Lord, C
Type
Thesis or Dissertation
Metadata
Show full item recordAbstract
The PSMC3IP MND1 heterodimer promotes RAD51 and DMC1-dependent D loop formation during meiosis in yeast and mammalian organisms. For this purpose, it catalyses the DNA strand exchange activities of the recombinases. Interestingly, in a panel of genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, I found that depletion of either PSMC3IP or MND1 caused sensitivity to clinical Poly (ADP Ribose) Polymerase inhibitors (PARPi). 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. Although replication fork reversal is also affected, the epistatic relationship between PSMC3IP-MND1 and BRCA1 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.
Collections
Research team
Gene Function
Language
eng
License start date
2023-10-10
Citation
2023
Publisher
Institute of Cancer Research (University Of London)