Endogenous DNA damage and its repair during haematopoiesis

Endogenous DNA damage is an important and dominant cause for the accumulation of mutations in all
organisms. This can be seen in the mutation signatures associated with cells obtained from aged animals and in
most cancers. The established factors and processes that cause endogenous DNA damage are oxygen, water,
structured DNA and DNA replication and transcription. However, a fundamental question is whether there are
other factors that are prevalent drivers for endogenous DNA damage and DNA repair pathways mitigate against
such damage. Our research has identified that simple aldehydes such as formaldehyde and acetaldehyde are
produced in our cells that can cause DNA damage possibly through the formation of DNA crosslinks. We
uncovered that a two-tier protection mechanism (aldehyde detoxification and DNA repair) ensure that these
metabolites do not cause DNA damage and mutations.

We aim to explain the physiological purpose for DNA repair, specifically why certain cell lineages and tissues are
dependent on specialised DNA repair pathways. Our foundational discovery is that two simple reactive aldehydes
(acetaldehyde and formaldehyde) are ubiquitous drivers of endogenous DNA damage which is repaired by DNA
crosslink repair. We established how we are protected from these endogenous genotoxins, firstly by enzymes
such as ALDH2 or ADH5 (Tier-1 protection) that detoxify them, and secondly by DNA crosslink repair by the
Fanconi anaemia (FA) proteins (Tier-2 protection). This Two-Tier protection mechanism is essential for the
renewal of blood because when it is inactivated in humans and mice, haematopoiesis ceases. We will continue to
define how Two-Tier protection ensures blood stem cell survival and integrity. We do not know when during the
development of these vital cells Two-Tier protection becomes essential, and how it then enables lifelong blood
production. We want to better understand how the p53 response impacts aldehyde-damaged stem cells. With our
collaborators, we will continue our mechanistic research to explain how FA crosslink repair functions and to
define the genomic land-scape of aldehyde-induced DNA damage and mutagenesis in haematopoietic cells.
Finally, we will examine how Tier-1 deficiency might have arisen to be a very common genetic trait in humans,
despite the fact that such individuals accumulate aldehydes and are therefore completely reliant on Tier-2
protection.