Marco Scheidegger, Carla Umansky.
Cellular metabolism can generate surplus compounds that may damage DNA leading to mutations and a pathological process. Aldehydes such as formaldehyde are among those metabolites. They derive from fundamental reactions such as the demethylation of histones and nucleic acids, or from the folic acid cycle.
Cells evolved two tiers of protection against formaldehyde. On one hand, the accumulation of reactive formaldehyde is prevented by expressing the enzyme alcohol dehydrogenase 5 (ADH5). The second tier consists of the DNA repair system “Fanconi Anemia” that counteracts DNA damage generated by endogenous aldehydes. Animals deficient in ADH5 and in the “Fanconi Anemia” DNA repair system suffer from bone marrow failure, aplastic anemia, liver and kidney failure, and are prone to develop several types of cancer. This genetic interaction demonstrates the carcinogenic potential of endogenous formaldehyde.
Our laboratory is focused on understanding how the accumulation of endogenous formaldehyde can lead to carcinogenesis. We study the mechanisms that counteract this aldehyde by combining cell genetics, biochemistry and studies in mice. Understanding the mechanisms that detect, control and resolve the metabolic sources of cellular damage contributes to elucidate the origins of the carcinogenesis and to identify novel therapeutic targets that can be used in the treatment of this condition.
Publications related to this project
- Reingruber, H. and Pontel, L.B.
Formaldehyde metabolism and its impact on human health.
C Op Tox 9:28-34 (2018)
- 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.
Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism.
Nature 548(7669):549-564 (2017)
- Pontel, L.B., Rosado, I.V., Burgos, G., Garaycoechea, J., Yu, R., Arends, M., Chandrasekaran, G., Broecker, V., Wei, W., Liu, L., Swenberg, J., Crossan, G., Patel K.J.
Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen.
Mol Cell 60:177-88 (2015)