Core E: Models of Genome Instability and Aging

University Of Minnesota, Minneapolis MN

Investigators

Abstract

Genome instability, a primary hallmark of aging, is defined as DNA damage driven by exogenous genotoxin exposure or endogenous events (genotoxins produced through normal metabolic processes, oxidation, and hydrolysis), DNA replication errors (point mutations, insertions and deletions, base mismatches that are not corrected), errors in chromosome segregation, and activation of transposable elements. These events can occur anywhere in the genome including in telomeric DNA. Genotoxic stress chronically activates the DNA damage response (DDR), which drives cell fate decisions such as cellular senescence or apoptosis, both of which lead to attrition of functional parenchymal and stem/progenitor cells, with the former also driving chronic sterile inflammation. Alternatively, changes to the genomic sequence may contribute to aging by driving loss of expression of key gene products or producing transcriptional noise through epigenetic changes. Therefore, it is valuable to the field of aging biology to rigorously determine not only the extent of DNA damage with age, but also to evaluate other hallmarks of aging that are linked to genome instability that are more tractable to intervention. Core E has amassed a unique and large collection of human samples and murine models (and a tissue bank from the mice) in which there is a DNA repair defect. These models enable the analysis of the molecular, cellular, and organismal impact of spontaneous, endogenous DNA damage. These models are also hypersensitive to exogenous genotoxins, enabling the study of environmental or iatrogenic factors that contribute to normal or accelerated aging. Thus, the overall goal of this Models of Genome Instability and Aging Core E is to make these models available to the broader aging research community for careful examination of how genome instability is linked to other hallmarks of aging that are more amenable to geroscience strategies. We propose to provide access to primary and immortalized cells from human subjects with well-established genome instability disorders; provide access to mice, tissues, and primary cells from mice with well-established defects in genome maintenance including live mice for specific tissue collections or intervention studies; and generate novel mouse models and human cells to interrogate the impact of genome instability on other hallmarks of aging. The pre-existing resources in Core E have already supported the research of dozens of internal and external laboratories. Overall, Core E will provide and create biospecimens that dovetail seamlessly with workflows in the other MN NSC Research Resource Cores to measure DNA damage and repair, DDR, and epigenetic changes. We also have the expertise to prepare samples for sc/snRNAseq and spatial proteogenomics. Thus, this Core represents a novel resource to the field of aging biology to interrogate the mechanism behind how genome instability, a primary hallmark of aging, drives aging and disease, and is distinct but complementary to resources provided by existing NSCs.