How structured DNA drives epigenetic variationGroup Leader Page
During DNA replication the usually stable DNA duplex is unwound providing an opportunity for the exposed single strands to adopt non-B form structures such as hairpins, triplexes and quadruplexes, which can then impede DNA synthesis. The impediment of DNA synthesis generates regions of single stranded DNA, which can lead to both genetic and epigenetic changes 1,2. Epigenetic changes as a result of replication pausing are a relatively unexplored, but potentially, extremely important source of cellular variation.
Our recent work suggests that structure formation during DNA replication is a very frequent event, even at sequences previously considered innocuous. We have shown that this apparently inert behaviour results from active measures taken by the cell to disassemble secondary structures and mitigate their effects 3-5.
However, exactly how DNA secondary structure formation is driven, detected and resolved by the replisome and how it leads to loss of epigenetic information remains unclear. The project will use somatic cells genetics, coupled with in vitro, deep-sequencing and bioinformatic approaches to understand how model structure-forming sequences destabilise gene expression in dividing cells.
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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.
- Lerner, L. and Sale, J.E.(2018).
Replication of G quadruplex DNA.
Genes (Basel) 10(2). pii E95. doi: 10.3390/genes10020095
- 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.
- Šviković, S., Crisp, A., Tan-Wong, S.M., Guilliam, T.A., Doherty, A.J., Proudfoot, N.J., Guilbaud, G. and Sale J.E. (2019).
R-loop formation during S phase is restricted by PrimPol-mediated repriming.
EMBO J. 38(3). pii: e99793, doi:10.15252/embj.201899793.