Targeting transcription-regulating cyclin dependent kinase 12 for the treatment of breast cancer

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dc.availability.bitstreamembargoed
dc.check.date2026-05-31
dc.contributor.advisorKrajewska, Malgorzataen
dc.contributor.authorBurns, Martha
dc.date.accessioned2023-01-27T11:32:33Z
dc.date.available2023-01-27T11:32:33Z
dc.date.issued2022-11-27
dc.date.submitted2022-11-27
dc.description.abstractCyclin-dependent Kinase 12 (CDK12) with its binding partner Cyclin K regulates transcription through phosphorylation of RNA Polymerase II (RNA Pol II) at serine 2. Previous work showed that inhibition of CDK12 leads to decreased expression of DNA damage response (DDR) genes and sensitizes cancer cells to DNA damage-inducing agents. However, the exact mechanism by which this is achieved remains unclear. This study aimed to investigate CDK12 as a therapeutic target in breast cancer and to identify new drug combinations involving the inhibition of CDK12 and clinically relevant inhibitors of DNA repair. We demonstrated that CDK12 inhibitor SR-4835 is cytotoxic in MCF-7 breast cancer cells at a low nanomolar concentration. The observed toxicity was associated with G2-M cell cycle arrest, increased apoptosis, and DNA damage. We showed that CDK12 inhibition had a minor effect on the phosphorylation of RNA Pol II at serine 2 indicating that global transcription was not affected. Interestingly, we observed that CDK12 inhibition resulted in decreased expression of chromodomain helicase DNA binding protein 2 (CHD2), a potentially new target of CDK12. Next, we tested the combination of CDK12 inhibition with inhibitors of DNA repair including inhibitors of PARP (olaparib) and CHK1 (AZD7762) using a colony formation assay. The preliminary results indicate that combining CDK12 and CHK1 inhibition will likely have greater therapeutic potential than the combination of CDK12 and PARP inhibition. Future studies are required to establish the exact role of CDK12 in transcription and DDR as well as to investigate further the potential of combining CDK12 and CHK1 inhibition in breast cancer.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationBurns, M. R. 2022. Targeting transcription-regulating cyclin dependent kinase 12 for the treatment of breast cancer. MRes Thesis, University College Cork.en
dc.identifier.endpage38en
dc.identifier.urihttps://hdl.handle.net/10468/14143
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2022, Martha Burns.en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectBiochemistryen
dc.subjectBreast canceren
dc.subjectGenome instabilityen
dc.titleTargeting transcription-regulating cyclin dependent kinase 12 for the treatment of breast canceren
dc.typeMasters thesis (Research)en
dc.type.qualificationlevelMastersen
dc.type.qualificationnameMRes - Master of Researchen
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