WEHI PhD Completion Seminar hosted by Dr Stephin Vervoort

Laura Corso
PhD Student – Vervoort Laboratory, Genetics and Gene Regulation division, WEHI

Transcription under stress: novel functions of the Integrator complex in transcriptional regulation

Davis Auditorium

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Including Q&A session      

RNA Polymerase II (RNAPII)-driven transcription is a highly controlled process important for normal development and homeostasis and has been found to be dysregulated in human disease including neurological disorders, autoimmunity and cancer. To this end, the stages of RNAPII- driven transcription need to be tightly regulated by many factors including large macromolecular complexes such as Integrator.

Integrator is a large complex comprising 15 subunits involved in the regulation of initiation, pausing but also termination of transcription. With its endonuclease and phosphatase enzymatic activities, Integrator plays a critical role in the premature termination of paused RNAPII via antagonising CDK9 pause-release activity. Despite much progress has been done in characterising the Integrator complex, the specific function of its different submodules remains poorly understood.

In this talk, I will describe the discovery of a non-canonical Integrator complex and a new mechanism of its recruitment via a combination of genomics, proteomics and CRISPR knock-out screening techniques. We find that the paralogue of Integrator subunit INTS6, INTS6-Like (INTS6L), can integrate in the complex and has redundant functions to INTS6. However, INTS6 and INTS6L are imperfect paralogues because they do not share the CDK9 antagonism activity. Further, we show that the Integrator subunit INTS12 is the factor that glues NELF to Integrator thus preventing the release of defective RNAPII molecules into elongation.

Overall, dissecting the Integrator complex will lead to a better understanding of RNAPII-transcription and to the identification of new therapeutic targets in diseases where the regulation of this process fails.

All welcome!