Aldehyde induced DNA damage in stem cells and their role in epithelial carcinogenesis

Background Prior work from my and other labs over the past decade and a half has shown that aldehydes, small reactive by-products of metabolism, are potent endogenous drivers of DNA damage, and that two tiers of protection operate in living systems to defend against them: Tier 1 (primarily reliant on glutathione-based systems and aldehyde dehydrogenase enzymes) provides metabolic detoxification that neutralise aldehydes before they can cause damage , while tier 2 consists of DNA repair pathways that resolve aldehyde-derived lesions blocking replication or transcription.

We have shown that haematopoietic stem cells require protection against acetaldehyde (which can derive from alcohol consumption as well as other, endogenous sources) as well as formaldehyde (produced in a range of cellular reactions) by the tier-1 enzymes ALDH2 and ADH5 respectively as well as the tier-2 Fanconi Anaemia (FA) DNA repair pathway (thought to resolve DNA interstrand crosslinks).

While animal models of FA deficiency show little overt pathology except for infertility in contrast to human patients with mutations in FA genes, the compound two-tier deficient model faithfully recapitulates most aspects of the human disease, including attrition of haematopoietic stem cells, bone marrow failure, and increased leukaemia predisposition.

This firmly established endogenous aldehydes as drivers of carcinogenesis.

Aims We now want to uncover how such aldehyde-induced DNA damage occurs, how it is repaired, and whether it promotes carcinogenesis in epithelial tissues. - Specifically, in ALDH2-deficient mice we observe elevated levels of acetaldehyde in the absence of exogenous ethanol, and wish to study where this comes from (WP1), and at what stages and in which cells protection by ALDH2 is required to protect integrity of haematopoietic stem cells. - Building on our discovery of the existence of an FA-independent repair pathway for acetaldehyde crosslinks, we set out to ask whether this is also true for other aldehyde-derived crosslinks ) and set out to identify the factors constituting the alternative repair pathway (WP2). - Epidemiological data suggests that deficient aldehyde protection predisposes to epithelial cancers particularly in the oral cavity and can also lead to liver cancer.

We therefore propose to construct models lacking two-tier protection in squamous epithelia (WP3), as well as the liver and ask whether systemic detoxification can protect tissues in trans(WP4) Methods We will use a combination of mouse and cellular genetics, biochemistry and other multi omic methods.

How the results of this research will be used publications, therapeutic leads