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dc.contributor.advisorLord C
dc.contributor.authorZelceski, A
dc.contributor.editorLord, C
dc.date.accessioned2023-10-10T13:33:42Z
dc.date.available2023-10-10T13:33:42Z
dc.date.issued2023-10-10
dc.identifier.citation2023en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/6010
dc.description.abstractThe 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.
dc.language.isoengen_US
dc.publisherInstitute of Cancer Research (University Of London)en_US
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserveden_US
dc.titleMND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cellsen_US
dc.typeThesis or Dissertation
dcterms.accessRightsPublic
dc.date.updated2023-10-10T13:32:17Z
rioxxterms.versionAOen_US
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserveden_US
rioxxterms.licenseref.startdate2023-10-10
rioxxterms.typeThesisen_US
pubs.organisational-groupICR
pubs.organisational-groupICR/Primary Group
pubs.organisational-groupICR/Primary Group/ICR Divisions
pubs.organisational-groupICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-groupICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-groupICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-groupICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-groupICR/Students
pubs.organisational-groupICR/Students/PhD and MPhil
pubs.organisational-groupICR/Students/PhD and MPhil/18/19 Starting Cohort
icr.researchteamGene Functionen_US
dc.contributor.icrauthorZelceski, Anabel
uketdterms.institutionInstitute of Cancer Research
uketdterms.qualificationlevelDoctoral
uketdterms.qualificationnamePh.D
icr.provenanceDeposited by Mr Barry Jenkins (impersonating Miss Anabel Zelceski) on 2023-10-10. Deposit type is initial. No. of files: 1. Files: A Zelceski PhD Thesis redacted.pdf
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePh.D


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