WEHI PhD Completion Seminar hosted by Dr Stephin Vervoort

Oliver Ozaydin
PhD Student – Vervoort Laboratory, Genetics and Gene Regulation division, WEHI

Termination dynamics dictate response to transcription elongation stress in cancer

Davis Auditorium

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Including Q&A session            

RNA polymerase II (RNAPII) transcription progression is governed by cyclin-dependent kinases (CDKs), which are frequently implicated in human disease including cancer. CDK12 loss is known to induce widespread elongation stress, leading to premature transcript termination and reduced RNAPII processivity.

Recurrent CDK12 mutations disproportionately aJect DNA damage response genes which creates a vulnerability in up to 12% of breast, bladder, colorectal and endometrial cancers. Despite this, little is known about executors of premature transcript termination under elongation stress which in turn may contribute to cancer progression.

This talk focuses on the discovery of a SCAF4/UBE3D/CPSF3  termination axis via genomewide CRISPR screening, genomics and proteomics techniques. We find that abrogation of axis members results in widespread resistance to elongation stress and restores full length transcription in over 60% of genes that are disproportionately long and AT-rich. We also find that axis member loss increases RNAPII elongation rates, providing an unexplored link between termination factors and RNAPII elongation rate dynamics.

Overall, we identify factors underpinning premature termination of RNAPII under elongation stress. Furthermore, these findings highlight potential mechanisms that may drive therapeutic resistance to small molecule inhibitors in preclinical development for CDK12-driven cancers.

All welcome!