Dr Sarah Allinson
Office C19 / Lab A27
Division of Biomedical and Life Sciences
Faculty of Health and Medicine
Tel: +44 1524 593922
Fax: +44 1524 593192
Cellular DNA is inherently unstable and is continually undergoing damage and degradation. Such damage can be caused by exposure to environmental carcinogens and also as a consequence of normal cellular metabolism, for example via the production of reactive oxygen species (ROS). My research is aimed at understanding the cellular response to DNA damage, with particular emphasis on the base excision repair (BER) and single strand break repair (SSBR) pathways.
Understanding how DNA repair is regulated at the level of single repair events and also within the cell as a whole can aid our understanding of inter-individual variation in cancer susceptibility and hopefully provide clues as to how repair in tumour cells may be attenuated to render cancer treatments more effective. With this aim in mind, there are a number of projects currently in progress in my lab.
Mechanistic studies of DNA repair
DNA repair pathways are multi-step processes involving a number of different enzymes and a network of protein-protein interactions. My research on DNA repair is aimed at understanding how the BER and SSBR pathways are co-ordinated and also how their efficiency might be affected by environmental carcinogens such as heavy metals. Through the detailed characterisation of repair of model DNA substrates by purified recombinant enzymes and cell extracts, facilitated by techniques such as site-directed mutagenesis, siRNA and protein-DNA interaction assays, we aim to gain a new mechanistic insight into how damaged DNA is repaired in vivo.
We have applied these methods to the study of the bifunctional SSBR enzyme, polynucleotide kinase (PNK). We were able to show that its two activities, kinase and phosphatase, were inter-dependent - with the phosphatase activity taking precedence over the kinase activity. More recently, we have shown that both activities of PNK are inhibited by the heavy metal carcinogen, cadmium.
In recent years it has become increasingly evident that the enzyme poly(ADP-ribose)polymerase (PARP-1) exerts a significant effect on DNA repair efficiency through both its high affinity for repair intermediates and its physical and functional interaction with many other key DNA repair enzymes. A major focus of my research is therefore aimed at understanding the mechanism of PARP-1 involvement in DNA repair.
The cellular response to UVA exposure
In collaboration with Trevor McMillan's group we are currently investigating the effects of UVA exposure on human cells. Originally thought not to be a significant risk factor for skin cancer, UVA is now believed to contribute as much as 10-20% of the cancer-causing dose of sunlight. UVA induces DNA damage indirectly via photosensitiser-mediated production of ROS. One area of research that we are currently actively pursuing involves characterising the effects of UVA on stress response pathways and seeing how they differ from those induced by shorter wavelength UVB.
Development of a novel bioassay for UVA-induced skin damage in collaboration with Trevor McMillan. See here for further details or email me at the address above.
BIOL437 Molecular Basis of Cancer: Module organiser and lecturer
BIOL463 Cell Biology Research Skills: Lecturer
BIOL121 Impact of Microbes: Lecturer
BIOL253 Genetics: Lecturer
Special Study Module convenor on the Medicine MBChB degree
Whiteside, J.R., Allinson, S.L. & McMillan, T.J. (2011) “Timeframes of UVA-induced bystander effects in human keratinocytes” Photochem. Photobiol. (in press)
Allinson, S.L. (2010) “DNA end-processing enzyme polynucleotide kinase as a potential target in the treatment of cancer” Future Oncol. 6 1031-1042 [Pubmed]
Whiteside, J.R., Box, C.L., McMillan, T.J. & Allinson, S.L. (2010) “Cadmium and copper inhibit both DNA repair activities of polynucleotide kinase” DNA Repair 9 83-89 [Pubmed]
Ridley, A.J., Whiteside, J.R., McMillan, T.J. & Allinson, S.L. (2009) “Cellular and sub-cellular responses to UVA in relation to carcinogenesis” Int. J. Rad. Biol. 85 177-195 [Pubmed]
Parsons, J.L., Tait, P.S., Finch, D., Dianova, I.I., Allinson, S.L. & Dianov, G.L. (2008) “CHIP-mediated degradation and DNA-damage dependent stabilization regulate base excision repair proteins” Molecular Cell 29 477-487 [Pubmed]
Jiao, H., Allinson, S.L., Walsh, M.J., Hewitt, R., Cole, K.J., Phillips, D.H., & Martin, F.L. (2007) “Growth kinetics in MCF-7 cells modulate benzo[a]pyrene-induced CYP1A1 up-regulation” Mutagenesis 22 111-116 [Pubmed]
Dobson, C.J., & Allinson, S.L. (2006) “The phosphatase activity of polynucleotide kinase takes precedence over its kinase activity in the repair of single strand breaks” Nucleic Acids Res. 34 2230-2237 [Pubmed] [Full Text]
Parsons, J.L., Dianova, I.I., Allinson S.L., & Dianov G.L. (2005) “DNA polymerase β promotes recruitment of XRCC1-Ligase IIIα to sites of base excision repair” Biochemistry 44 10613-10619 [Pubmed]
Parsons, J.L., Dianova, I.I., Allinson, S.L., & Dianov, G.L. (2005) “Poly (ADP-ribose) polymerase-1 protects excessive DNA strand breaks from deterioration during repair in human cell extracts” FEBS J. 272 2012-2021 [Pubmed] [Full Text]
Sleeth, K.M., Dianova, I.I., Allinson, S.L., Parsons, J.L., Breslin, C., Caldecott, K.W. & Dianov, G.L. (2004) “XRCC1-DNA polymerase β interaction is required for efficient base excision repair” Nucleic Acids Res. 32 2550-2555 [Pubmed] [Full Text]
Allinson, S.L., Sleeth, K.M., Matthewman, G.E. & Dianov, G.L. (2004) “Orchestration of base excision repair by controlling the rates of enzymatic activities” DNA Repair 3 23-31 [Pubmed]
Dianov, G.L., Sleeth, K.M., Dianova, I.I. & Allinson, S.L. (2003) “Repair of abasic sites in DNA” Mutation Res. 531 157-163 [Pubmed]
Allinson, S.L., Dianova, I.I. & Dianov, G.L. (2003) “Poly (ADP-ribose) polymerase in base excision repair: always engaged but not essential for DNA damage processing” Acta Biochim. Pol. 50 169-179 [Pubmed] [Full Text]
Allinson, S.L., Dianova, I.I. & Dianov, G.L. (2001) “Polymerase β is the major dRP lyase involved in repair of oxidative base lesions in DNA by mammalian cell extracts” EMBO J. 20 6919-6926 [Pubmed] [Full Text]