Do clashes between transcription and replication drive immune evasion in the African trypanosome?

Friday 24 November 2017, 1.00PM

Speaker: Dr Richard McCulloch, Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow

During transcription, nascent RNA can bind the template strand of unwound DNA, forming stable R-loops. Several proteins prevent and remove R-loops, including ribonuclease H (RNaseH). Although threatening to genome stability and function, R-loop- forming sequences can be powerful regulators of DNA replication, gene expression and recombination.
 
Trypanosoma brucei, a diverged eukaryotic microbe, displays near universal multigenic transcription, with ~8000 RNA Polymerase II-transcribed genes co-transcribed from a small number (~200) of polycistronic transcription units (PTUs). In addition, and highly unconventionally, survival of T. brucei in the mammal relies upon expression of a Variant Surface Glycoprotein (VSG) coat from one of ~15 RNA PolI-transcribed telomeric PTUs. VSG coat changes mediate host immune evasion and are executed by transcriptional switches between the VSG PTUs and by recombination events involving a silent store of ~2000 VSGs.
 
We have localised R-loops in the T. brucei genome using DRIP-seq in the presence and absence of both T. brucei RNaseH enzymes, RH1 and RH2. In the RNA PolII-transcribed ‘core’ genome, R-loops populate the intergenic regions throughout the PTUs, localising with sites of polyadenylation. Loss of RH2, unlike RH1, is lethal, results in cell cycle arrest and accumulation of DNA damage associated with transcription initiation. Loss of either RNaseH enzyme alters VSG expression control, with RH1 null mutants displaying increased R-loop signal across the VSG PTUs, suggesting a model for VSG coat switch initiation. Overall, we reveal distinct roles for two RNaseH enzymes in T. brucei and show that R-loops contribute to genome-wide gene expression and immune evasion.

The host for this seminar is Professor Jeremy Mottram 

Location: K018

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