Identifying sequences that trip up DNA replication and how they cause genetic instability
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The speed and accuracy of DNA replication is frequently challenged by problems on the DNA template, for instance damaged bases. However, the DNA itself can also present a significant impediment to processive replication through the formation of secondary structures[1,2]. By causing DNA synthesis to stall, these structures can promote the genetic changes that drive cancer.
The aim of this project is to identify sequences in the genome that cause DNA synthesis to pause and to understand the circumstances under which this leads to genetic instability.
The project will use a unique approach to monitoring replication pausing at specific sequences in vivo that exploits local changes in the epigenome as a ‘lens’ to monitor delays in replication of specific structure-forming sequences in vivo in avian and human cells[3-5]. This will be coupled with reporters that monitor genetic instability at these sequences in different genetic backgrounds both locally and genome wide.
The work will shed light on the mechanisms by which cells avoid genetic changes at naturally occurring replication barriers.
- Šviković, S. and Sale J.E. (2017).
The effects of replication stress on S phase histone management and epigenetic memory
J. Mol. Biol. 429, 2011-2029. doi:10.1016/j.jmb.2016.11.011.
- Wickramasinghe, C.M., Arzouk, H., Frey, A., Maiter, A. & Sale, J.E. (2015).
Contributions of the specialised DNA polymerases to replication of structured DNA.
DNA Repair 23, 83-90. doi: 10.1016/j.dnarep.2015.01.004.
- Schiavone, D., Guilbaud, G., Murat, P., Papadopoulou, C., Sarkies, P., Prioleau, M.-N., Balasubramanian, S. and Sale, J.E. (2014).
Determinants of G quadruplex-induced epigenetic instability in REV1-deficient cells.
EMBO J. 33, 2507-20.
- Schiavone, D., Jozwiakowski, S.K., Romanello, M., Guilbaud, G., Bailey, L.J., Sale, J.E. & Doherty, A.J. (2016).
PrimPol is required for replicative tolerance of G quadruplexes in vertebrate cells.
Molecular Cell 61, 161-169. doi: 10.1016/j.molcel.2015.10.038.
- Guilbaud, G.*, Murat, P.*, Recolin, B., Campbell, B.C., Maiter, A., Sale, J.E.and Balasubramanian, S. (2017)
Local epigenetic reprogramming induced by G quadruplex ligands.
Nature Chemistry 9, 1110-1117.