Mechanisms of replication-induced genome instability

Antony M. Carr1, Izumi Miyabe, Kenichi Mizuno, Yasukazu Daigaku, Saed Mohebi, Johanne M. Murray, Andrea Keszthelyi.
1Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, BN1 9RQ, UK


A common feature of cancer cells is genetic instability. We are interested in how this genetic instability occurs. When cancer is initiated by oncogene expression, DNA replication is perturbed and cells experience “oncogene-induced stress” (OIS) during which replication generates DNA damage which activates the p53 checkpoint. This results in a barrier to cancer progression that must be overcome (i.e. through loss of p53) if carcinogenesis is to progress.
OIS can result in the replisome dissociating from the fork (collapsed fork), or the fork structure to break (broken fork). In these cases, replication restart can proceed by either homologous recombination (HR) or microhomology-primed re-initiation (FoSTeS/MMBIR). Our previous work has demonstrated that HR-restarted DNA replication is intrinsically error prone. We are currently examining the consequences of replicating a region of DNA with a fork that has been correctly restarted by HR. Using DNA polymerase mutants that incorporate excess ribonucleotides we have shown that, following replication restart by HR-dependent mechanisms within S phase, replication is semi-conservative and both strands are synthesised by polymerase delta. We have developed a protocol (Ribo-Seq) to map, genome-wide, the usage of Polymerase delta and Polymerase epsilon. Our data plot, at very high resolution, the location of the replication origins and identify regions of the genome where there is increased usage of polymerase delta to replicate the duplex DNA. Such sites may represent regions prone to genome instability.


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Dr Patrick Varga-Weisz
The Brian Heap Seminar Room