LABORATORY MEMBERS
Thomas Ashton
Takabumi Inagawa
Anna Olsen
Sovan Sarkar
Lonnie Swift
Anderson Wang
Thomas Ward
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Drugs
that produce covalent interstrand cross-links in DNA remain important
in cancer treatment. However, both inherent and clinically acquired
resistance are a problem, and there is growing evidence that the
efficiency of DNA cross-link elimination influences tumour response.
Consequently a major goal of this laboratory is to define the DNA
repair pathways acting on interstrand cross-links. We have focussed on
the yeast Saccharomyces cerevisiae as a model system to understand
these pathways, but more recently have begun to translate our
findings into studies of mammalian cells. We have recently
characterised an interstrand cross-link pathway that relies upon the
ability of specialised ‘translesion’ polymerases to copy
past cross-links that have been subject to incision by the nucleotide
excision repair apparatus (see figure).
Related to our studies
of cross-link repair, we also have a major interest in a family of DNA
repair factors that contain a metallo--lactamase structural domain.
These factors, including yeast Pso2 and human Snm1, play an important
role in the post-incision processing of cross-link repair
intermediates, but the mechanistic basis of this is not well understood.
Finally, we also study
the role of two closely related ATPase chromatin remodelling complexes
in nucleotide excision repair. We have recently found that the yeast
Ino80 and Swr complexes play a co-operative role needed for nucleotide
excision repair to occur efficiently in cellular chromatin. We are now
addressing whether these highly-conserved complexes play an analogous
role in mammalian cells.
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RECENT
PUBLICATIONS
Hazrati
A, Ramis-Castelltort M, Sarkar S, Barber LJ, Schofield CJ, Hartley JA,
McHugh PJ.Human SNM1A suppresses the DNA repair defects of yeast pso2
mutants. DNA Repair. 2007, in press.
Sarkar S, Davies AA, Ulrich HD, McHugh PJ.DNA interstrand crosslink
repair during G1 involves nucleotide excision repair and DNA polymerase
.EMBO J. 2006 25(6):1285-94.
Barber LJ, Ward TA, Hartley JA, McHugh PJ. DNA interstrand cross-link
repair in the Saccharomyces cerevisiae cell cycle: overlapping roles
for PSO2 (SNM1) with MutS factors and EXO1 during S phase. Mol
Cell Biol. 2005 25(6):2297-309
Lambert, S., Mason, S., Barber, L., Hartley, J.A., Carr, A.M. and McHugh
P.J. (2003) The Schizosacch- aromyces pombe checkpoint response to DNA
interstrand cross-links. Mol. Cell.Biol. 23, 4728-737.
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