Dr Marco Saponaro, a Birmingham Fellow in the Institute of Cancer and Genomic Sciences, has been awarded a three-year BBSRC Responsive Mode grant of £568,010.46 to determine the interplay between RNA Polymerase II transcription and DNA replication.
The DNA in each cell is used as a stamp by two processes, RNA transcription and DNA replication. Transcription allows expressing the genetic information encoded in the genome, while replication creates two identical copies of the genome to pass on to daughter cells.
However, as both transcription and replication are formed by big molecular machineries, the DNA can only be engaged by one of them at any given time. Consequently, collisions and conflicts between the transcription and replication machineries are associated with reciprocal interference, that can lead to replication stress and genome instability.
"For a long time we have known that transcription is a great endogenous source of DNA damage in cells," Dr Saponaro explains.
"Genome instability is massively increased even more in cases with defective transcription. Such defective transcription occurs when there are mutations or deregulations of transcription-associated factors, or because of oncogenic signalling, linking directly defective transcription to human diseases.
"However, although all what we know about the impact of transcription on replication and genome stability maintenance, we still do not know how these two processes are coordinated in human cells in normal conditions to avoid conflicting instances. This BBSRC grant will allow us to shed light on the reciprocal impact of transcription and replication."
Through a systematic approach that will combine genome wide approaches with molecular and cellular biology techniques, we will determine how and where transcription and replication affect each other, and also what is the cellular response to these conflicting instances. It will consent us to define the interplay between these two processes, in order to understand how this relationship gets compromised in contexts with defective transcription.
The BBSRC application was supported by previous funding from the University of Birmingham, the Wellcome Trust and the Royal Society.