We study endogenous DNA damage and its impact on the function of vertebrate stem cells and the ageing process. Our recent work has shown that metabolism releases reactive aldehydes that are a potent source of such endogenous DNA damage. Mammals are protected against these genotoxic metabolites by first eliminating them through oxidising enzymes, and secondly by repairing the DNA damage they cause.
Kaplan-Meier graph showing survival of mice lacking two-tier protection against acetaldehyde (red) or formaldehyde (green) compared to allelic controls
This two-tier protection mechanism has a fundamental role in ensuring intact embryonic development, the renewal of blood and the function of vital metabolic organs. When the 2nd tier protection fails in humans, it causes the genetic illness Fanconi anaemia – such individuals accumulate endogenous DNA damage that causes defective development, loss of blood production and an enormous life-time risk of cancer.
Our current research aims to define the origins and identity of genotoxic metabolites, how cells remove them, the nature of the DNA damage they cause and how this damage is repaired. We are also want to understand how certain stem cells and organ systems are damaged by these sources of endogenous DNA damage, and the consequences of this to an organism.
- 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 548: 549-554
- 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.
Molecular Cell 60: 177-188
- Oberbeck, N., Langevin F., King, G., Wind, N., Crossan G.P. and Patel K.J. (2014)
Maternal aldehyde elimination during pregnancy preserves the fetal genome.
Molecular Cell 55(6): 807 – 817
- Hodskinson, M.G., Silhan, J., Crossan, G.P., Garaycoechea, J.I., Mukherjee, S., Johnson, C.M., Schärer, O.D. and Patel, K.J. (2014)
Mouse SLX4 is a tumour suppressor that stimulates the activity of the nuclease XPF-ERCC1 in DNA crosslink repair.
Molecular Cell 54(3): 472-484
- Garaycoechea, J.I., Crossan, G.P., Langevin, F., Daly, M., Arends, M.J. and Patel, K.J. (2012)
Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function.
Nature 489: 571-575
- Langevin, F., Crossan, G.P., Rosado, I.V., Arends, M.J. and Patel, K.J. (2011)
The Fanconi Anaemia DNA repair pathway counteracts the toxic effects of naturally produced aldehydes.
Nature 375: 53-58
- Laura Brandt
- Lee Mulderrig
- Meng Wang