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Transcription-replication crosstalk

Primary Supervisor: Dr Marco Saponaro, Institute of Cancer and Genomic Sciences

Secondary supervisor: Dr Agnieszka Gambus

PhD project title: Transcription-replication crosstalk

University of Registration: University of Birmingham

Project outline:

Background:

RNA Pol II transcription and DNA replication are the two essential processes that use as a substrate the DNA in our cells. This allows cells to express the content of their genetic information, and to propagate these instructions on to daughter cells. However, DNA can be engaged only by one of these processes at any given time. Therefore, transcription can impair DNA replication inducing DNA damage and genome instability. In contexts of defective transcription this instability is furthermore greatly increased. Importantly, transcription-induced genome instability has also a direct impact on human health, as associated with cancer development and neurological disorders. We have now uncovered the first details of how exactly transcription and replication affect each other, and want to expand our understanding characterising further the crosstalk between these two processes.

Aims of the project and methods:

For all these reasons, we are interested in investigating further the relationship between RNA Pol II transcription and DNA replication using a systemic approach.

  1. Genome-wide next generation sequencing analyses of both transcription and DNA replication;
  2. Cell biology studies to characterise the impact of the interference between transcription and replication on genome stability (immune-fluorescence staining of DNA damage sites, activation of the DNA damage response by immunoblotting);
  3. Functional studies to characterise the roles of factors involved in coordinating, and resolving conflicting situations, between these two processes (impact of the RNAi of specific factors on genome-wide coordination between transcription and replication and on the DNA damage levels).

The understanding of how these two processes affect each other is a problem at the basis of cell biology. However importantly, understanding the fine details of this crosstalk has broad ranging relevance for human health as well.

References:

  1. Saponaro et al., RECQL5 controls transcript elongation and suppresses genome instability associated with transcription stress. Cell 2014; doi: 10.1016/j.cell.2014.03.048
  2. Williamson et al., UV irradiation induces a non-coding RNA that functionally opposes the protein encoded by the same gene. Cell 2017; doi:10.1016/j.cell.2017.01.019

BBSRC Strategic Research Priority: Integrated Understanding of Health: Ageing

Techniques that will be undertaken during the project :

The student will have the opportunity to acquire a multiplicity of techniques including: cell culture; genome wide next generation sequencing approaches like RNA-Seq, ChIP-Seq and Repli-Seq; RNAi techniques; fluorescent and visual microscopy; immunoblotting and immunofluorescence, molecular cloning, protein biochemistry.

Contact: Dr Marco Saponaro, University of Birmingham