K J Patel
Genotoxic metabolism and the DNA damage response in stem and cancer cells
Group Leader page
Our work has shown that metabolism both generalized and intrinsic to blood stem cells unleashes reactive molecules such as the aldehydes – formaldehyde and acetaldehyde. Such metabolites can damage DNA, causing the stem cells to die or to accumulate cancer causing mutations. Fortunately a two tier protection mechanism ensures that these aldehydes do not irreversibly damage stem cells. Tier 1 protection consist of enzymes that degrade or inactivate metabolites whilst tier 2 consists of DNA repair mechanisms the fix metabolite inflicted DNA damage. The aims of the research project are:
- To identify novel tier 1 protection enzymes and their interaction with specific DNA repair pathways –by way of genome wide CRISPR/Cas genetic screens in primary stem cells and cell lines.
- To identify the new genotoxic metabolites removed by such novel tier 1 enzymes.
- To define approaches by which inhibition of two-tier protection might be exploitable to kill certain cancer cells.
These three broad questions will be addressed by using state of the art genetics and systems biology. It is anticipated that the answer to these questions may have implications for the biology of stem cells, the ageing process and shed light on the origin of certain cancers.
Garaycoechea, J.I., Crossan, G.P., Langevin, F., Mulderrig, L., Louzada, S., Yang, F., Guilbaud, G., Park, N., Roerink, S., Nik-Zainal, S., Stratton, M.R., Patel, K.J. (2018)
Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells.
Nature 553: 171-177
Burgos-Barragan, G., Wit, N., Meiser, J., Dingler, F.A., Pietzke, M., Mulderrig, L., Pontel, L.B., Rosado, I.V., Brewer, T.F., Cordell, R.L., Monks, P.S., Chang, C.J., Vazquez, A., Patel, K.J. (2017)
Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism.
Nature. 2017 Aug 31;548(7669):549-554. doi: 10.1038/nature23481. Epub 2017 Aug 16.
Pontel, L.B., Rosado, I.V., Burgos-Barragan, G., Garaycoechea, J.I., Yu, R., Arends, M.J., Chandrasekaran, G., Broecker, V., Wei, W., Liu, L., Swenberg, J.A., Crossan, G.P., Patel, K.J. (2015)
Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen.
Mol Cell. 2015 Oct 1;60(1):177-88. doi: 10.1016/j.molcel.2015.08.020. Epub 2015 Sep 24.