Laura Corso presented her PhD completion seminar on novel functions of the Integrator complex in transcriptional regulation. The seminar, hosted by Dr. Stephin Vervoort at WEHI, focused on RNA Polymerase II (RNAPII)-driven transcription.
RNAPII-driven transcription is a highly controlled process essential for normal development and homeostasis. Dysregulation of this process has been observed in human diseases, including neurological disorders, autoimmunity, and cancer. The Integrator complex, comprising 15 subunits, plays a critical role in regulating the initiation, pausing, and termination of transcription. Its endonuclease and phosphatase activities are involved in the premature termination of paused RNAPII by antagonizing CDK9 pause-release activity.
Corso's research detailed the discovery of a non-canonical Integrator complex and a new mechanism for its recruitment, identified through genomics, proteomics, and CRISPR knock-out screening techniques. Specific findings include:
- The paralogue of Integrator subunit INTS6, INTS6-Like (INTS6L), can integrate into the complex and exhibits redundant functions to INTS6.
- INTS6 and INTS6L are considered imperfect paralogues as they do not share the CDK9 antagonism activity.
- The Integrator subunit INTS12 is identified as the factor that links NELF to Integrator, thereby preventing the release of defective RNAPII molecules into elongation.
Dissecting the Integrator complex is anticipated to advance the understanding of RNAPII-transcription and contribute to the identification of new therapeutic targets in diseases where this regulatory process is impaired.