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Title: Role of R-loops in pause-dependent transcriptional termination of RNA polymerase II
Author: Skourti-Stathaki, Konstantina
ISNI:       0000 0004 2744 5720
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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Transcription termination of RNA polymerase II (Pol II) in mammals requires a functional poly(A) signal and either downstream pause sites or co-transcriptional cleavage (CoTC) sequences together with 3’transcript degradation by the nuclear 5’-3’ exonuclease Xrn2. However the molecular mechanism of pause-dependent transcriptional termination is not yet fully understood. This thesis investigates the molecular role of R-loop structures in pause-dependent transcriptional termination of mammalian genes. The results described in Chapters 3 and 4 indicate that nascent transcripts form RNA/DNA hybrid structures (R-loops) behind elongating Pol II and are especially prevalent over G-rich pause sites positioned downstream of gene poly(A) signals. Senataxin, a helicase protein and the human homologue of the yeast Sen1, acts to resolve these R-loop structures and by so doing allows access of Xrn2 at 3’ cleavage poly(A) sites. This ultimately leads to efficient Pol II termination. In effect R-loops formed over G-rich pause sites, followed by their resolution by senataxin, are required for efficient pause-dependent transcriptional termination. In addition to this, the 3’ end processing factor, Pcf11 is also involved in this process. Experiments presented in the final part of this study reveal a link between R-loops and RNAi-dependent H3K9me2 formation over G-rich termination regions. Overall my results suggest that R-loop structures and the H3K9me2 repressive mark over pause regions are important features of Pol II pause-dependent transcriptional termination of mammalian genes.
Supervisor: Proudfoot, Nicholas Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biology (medical sciences) ; termination ; R-loops ; RNA polymerase II ; pause