Core C: DNA Damage and Epigentic Changes

University Of Minnesota, Minneapolis MN

Investigators

Abstract

SUMMARY– DNA DAMAGE AND EPIGENETIC CHANGES CORE C Tretyakova and Villalta The decline of organismal functions seen in the aging process is linked to specific genome instability, a primary hallmark of aging. Genome instability, in particular, DNA damage is recognized as a key event in driving not only cellular senescence, but also changes to the epigenome that are associated with aging. Although both endogenous and exogenous factors elicit DNA damage, of the sources of genome instability, spontaneous, endogenous DNA damage, arising as a consequence of normal physiologic processes, is by far and away the most common event, estimated to occur at a rate of ~40,000 events per cell per day. If not repaired, this DNA damage can drive a DNA damage response (DDR) that results in epigenetic changes, senescence with its inflammatory SASP and changes in other hallmarks of aging. Thus, the ability to characterize the diverse types of DNA adducts and epimutations involved in the aging process provides opportunities for the development of novel biomarkers of aging and allow for the development of new therapeutic strategies to delay aging and extend the health span. The MN NSC DNA Damage and Epigenetics Core C will offer a range of assays to quantify endogenous DNA damage, characterize the adductome, and detect epigenetic alterations in DNA including methylation and hydroxymethylation. Core C also will help identify novel DNA damage and epigenetic biomarkers of aging that then can assist biology of aging investigators. Specifically, Core C will provide quantitation of established age-related adduct-specific DNA damage including 8-oxo-dG, O6-methyl-dG, cyclo- dA, cyclo-dG, ԐdC, ԐdG, ԐdA, CM-dG, hydroxymethyl-dC, formyl-dC, HNE-dG and Thy-Tyr DNA-protein cross- links; perform DNA adductomic analysis to identify new DNA adduct biomarkers of aging; develop and validate new assays for age-related DNA adducts; characterize aging associated epigenetic changes, in particular, global DNA methylation and hydroxymethylation by LC-MS/MS and the distribution of DNA marks using Illumina Epic 850 DNA methylation array; and identify new epigenetic biomarkers of aging such as the novel epigenetic DNA mark N6-methyladenine. Core C is co-directed by Natalia Tretyakova, an expert in analysis of DNA adducts and epigenetic changes, and Peter Villalta, an expert in the analysis of DNA damage by mass spectrometry. Importantly, the Core will leverage existing operational UMN cores including the Analytical Biochemistry Shared Resource of the Masonic Cancer Center and the University of Minnesota Genomics Center. The Core also will provide training opportunities to young investigators and junior faculty on methodologies for analysis of DNA damage and the epigenome. Finally, Core C will work with the other two research cores to characterize genome instability and the DDR with aging in model systems including mice.