Patel Group: Two tier protection and metabolic genotoxicity during blood production

ketan.patel@imm.ox.ac.uk

500 million people in the world cannot clear acetaldehyde (asian alcohol flush) -"Tier 1 protection"

1 in 160,000 individuals cannot fix the DNA damage that acetaldehyde and formaldehyde causes (Fanconi Aanemia) -"Tier 2 protection "

We study endogenous DNA damage caused by metabolites and their 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. We protect ourselves against these genotoxic metabolites by removing them, and if this fails then by repairing the DNA damage they cause (two-tier protection against aldehydes). Kaplan-Meier graph showing survival of mice lacking two-tier protection against acetaldehyde which is the by product of alcohol metabolism (red in main image) or formaldehyde (green in main image) compared to allelic controls (Garraycochea et al Nature 2018, Pontel et al Mol Cell 2015, Garraycochea et al Nature 2012, Langevin et al Nature 2011).

This genetic observation led us to propose a two-tier protection mechanism (main image) which ensures that these simple aldehyde do not cause lasting damage particularly to the production of blood. 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.

Atlhough acetaldehyde is a by product of alcohol metabolism, the most prevalent aldehyde appears to be formaldehyde which you may recognise as a fixative for tissue samples etc. More recent research from our lab has shown that formaldehyde can be produced when the vitamin folic acid breaks down, however the cell also utilises this formaldehyde as source for one carbon metabolism which produces many molecules of life such as DNA bases and amino acids (Barragan et al Nature 2017). Thus nature converts a reactive endogenous toxin into an essential substrate for metabolism.

We wish to better understand where these aldehydes come from, how they damage DNA and how this is repaired (Rajendra et al Mol Cell 2015, Shakeel et al Nature 2019, Alcon et al Nature Strucural and Molecular biology 2019, Hodskinson et al Nature 2020), and how this damage corrupts blood production.

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