Julian Sale

Vertebrate mutagenesis and DNA damage tolerance

Szüts, D., Marcus, A.P., Himoto, M., Iwai, S. & Sale J.E. (2008).

REV1 restrains DNA polymerase zeta to ensure frame fidelity during bypass of a UV photoproduct in vivo.
Nucleic Acids Res. 36, 6767-80.

Edmunds, C.E., Simpson L.J. & Sale J.E. (2008)
PCNA ubiquitination and REV1 define temporally distinct mechanisms for controlling translesion synthesis
in the avian cell line DT40.
Mol. Cell 30, 519-29

Sarkies, P, Reams, C. Simpson, L.J. & Sale J.E. (2010)
Epigenetic instability caused by defective replication of structured DNA
Mol. Cell in press

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Group Members

Laura Simpson
Tammy Yulzary (Listovsky)
Caroline Malone
Charikleia (Harris) Papadopoulou
Davide Schiavone
Nick Brindle
Guillaume Guilbaud
Alexander Frey

My lab is interested in the mechanisms that alleviate arrested DNA replication and the impact their loss has on mutagenesis and on the maintenance of epigenetic memory through the recycling of histones during replication.

Replication can be arrested by DNA damage or by naturally occurring DNA secondary structures. We are particularly interested in translesion synthesis (TLS), which is mediated by specialised DNA polymerases and which is required for replication of both DNA damage and a particular secondary structure called a G quadruplex. Although TLS is potentially mutagenic it plays a critical role in normal cells and understanding its control is central to understanding cell transformation.

We study these processes using the powerful combination of vertebrate somatic cell genetics coupled with biochemical, biophysical and advanced optical microscopy techniques to monitor the molecular choreography of proteins and DNA at sites of stalled replication.

An outcome of one possible resolution of blocked replication: DNA damage-induced sister chromatid exchanges in DT40.

Individual DNA fibres from DT40 cells in which replication tracts have been labelled with halogenated nucleotides. The green and red portions each reflect 20 minutes of DNA synthesis. DNA damage has been added during the second (red) labelling period in the lower panel resulting in replication fork stalling.

MRC Laboratory of Molecular Biology