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 metabolites such as the aldehydes – formaldehyde and acetaldehyde. Such metabolites and in these cases simple aldehydes 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 these stem cells. Tier 1 protection consist of enzymes that remove such metabolites whilst tier 2 consists of DNA repair mechanisms the fix metabolite inflicted DNA damage. The aim of the research of the research projects are:
- To identify by way of genome wide CRISPER –Cas genetic screens in primary stem cells and cell lines new tier 1 protection enzymes and their interaction with specific DNA repair pathways.
- To identify new genotoxic metabolites that the new tier 1 enzymes remove.
- 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 genetic and system biological approaches. It is anticipated that the answer to these question may have implication of stem cell biology, the ageing process and the origin of certain cancers.
Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ. (2011)
Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice.
Nature. 2011 Jul 6;475(7354):53-8. doi: 10.1038/nature10192.
Garaycoechea JI, Crossan GP, Langevin F, Daly M, Arends MJ, Patel KJ. (2012)
Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function.
Nature. 2012 Sep 27;489(7417):571-5. doi: 10.1038/nature11368. Epub 2012 Aug 26.
Pontel LB, Rosado IV, Burgos-Barragan G, Garaycoechea JI, Yu R, Arends MJ, Chandrasekaran G, Broecker V, Wei W, Liu L, Swenberg JA, Crossan GP, Patel KJ. (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.
Burgos-Barragan G, Wit N, Meiser J, Dingler FA, Pietzke M, Mulderrig L, Pontel LB, Rosado IV, Brewer TF, Cordell RL, Monks PS, Chang CJ, Vazquez A, Patel KJ. (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.