Strategic endgames – modulating transcription termination to control gene expression (360G-Wellcome-218537_Z_19_Z)

Viruses employ various approaches to avoid host cell defence-mechanisms. In Herpes Simplex Virus 1 (HSV1) and Influenza A Virus (IAV) these include strategies to inhibit transcription termination. This leads to non-terminated readthrough transcripts, likely nuclear retained and untranslated. Exactly how viruses inhibit transcription termination, and how this promotes their survival and efficacy is currently unclear. Using my experience and expertise in transcription termination, I propose to systematically analyse the mechanism by which IAV alters 3’ end processing transcription termination and determine how this affects host gene expression. I will use biochemistry, molecular biology and structural biology, to identify the termination components affected by IAV, and reverse genetics to identify the IAV-component effecting termination inhibition. I will also employ sequencing of fractionated, cellular and ribosome-associated RNA to examine how virally- induced termination defects perturb mRNA-export and translation, as well as cell biology and genetics to identify the mechanisms and signalling cascades through which this change is realised. Finally, I will perform orthogonal studies in budding yeast to identify molecular mechanisms that can modulate the activity of transcription termination and RNA processing factors. Overall, my programme will scrutinize an under-explored yet fascinating mechanism to alter gene expression through modulation of transcription termination.