Proteotoxic Metabolites in Genome Instability and Disease

Summary Diverse exogenous and endogenous aldehydes produce aberrant adducts that, if left unrepaired, can promote genome instability and disease. Prevalent lifestyle choices as well as intrinsic metabolic dysfunctions and genetic exposures associated with cancer and aging have been linked to the accumulation of reactive aldehydes that produce persistent, genome-destabilizing DNA adducts. Inactivation of aldehyde clearance and DNA repair proteins leads to genome instability and cancer by rendering cells hypersensitive to formaldehyde- and acetaldehyde-induced DNA damage. Genotoxic DNA adducts are considered the de facto surrogates for aldehyde-related genome instability. However, another less studied mechanism of genome instability is defects in the folding of DNA repair proteins. In addition to damaging the DNA, aldehydes also modify proteins to produce aberrant protein adducts that cannot fold or function properly. Yet, the role of proteotoxic stress in aldehyde-induced genome instability remains enigmatic. Here, we hypothesize that aldehyde derived protein adducts target the central protein folding chaperone heat shock protein 90 (HSP90) in impairing the folding of critical DNA repair proteins that regulate genome stability. Our published finding that HSP90 can buffer (that is, mitigate) deleterious mutations in humans provided a system to compare side-by-side both the genotoxic and proteotoxic effects of aldehydes in cells and tumors. Using this system in preliminary work, we now show that mutations that HSP90-buffered mutations in DNA repair genes render genome instability conditional upon seemingly benign exposures to formaldehyde and acetaldehyde. The goal of the proposed research is to unravel mechanisms of HSP90-contingent genome instability elicited by reactive aldehydes. The rationale for this proposal is that understanding how aldehydes promote genome instability may reveal new universal approaches for risk stratification and management. This project will achieve this goal by employing innovative adductomics and functional genomics approaches strategically designed to 1) determine the mechanism of HSP90 impairment by formaldehyde and acetaldehyde, and 2) delineate the proteotoxic and genotoxic effects of aldehydes on genome instability in tumor xenografts. The successful completion of this project will define mechanisms linking genome instability, proteotoxic stress, and metabolic dysregulation, cellular hallmarks of disease that are traditionally studied in isolation. The proposed work will also evaluate protein adducts as comprehensive indicators of proteotoxicity and will probe the role of aldehydes as the ecological stressors that engage HSP90 function in driving genome instability in cells, tissues, and tumors. Achieving this will provide a framework and new tools for future studies to decipher gene-by-metabolite-by-environment relationships and to develop more efficacious individualized strategies for managing diverse aldehyde-related diseases, including many cancers.