Origins of Genome Instability in Progeria

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Hutchinson-Gilford Progeria Syndrome (HGPS) was the first identified premature aging syndrome caused by mutation of lamin A, a component of the nuclear lamina. HGPS patients typically die before the age of 20 and exhibit accelerated aging phenotypes. Mutant lamin A protein, also called progerin, directly disrupts the nuclear lamina, resulting in alteration of lamina-associated chromatin architecture, including increased senescence and sensitivity to DNA damaging agents. In particular, DNA damage response defects and increased genome instabilities have been observed in many progeroid syndromes and normal aged cells, thereby linking genome instability with aging. However, the reasons why alteration of the nuclear lamina causes genome maintenance defects is not well understood. Our recent results reveal a previously unknown origin of genome instability in progeria cells. Specifically, we observe that progerin expression results in an intrinsic increase in susceptibility to acquire DNA lesions. Our long-term goal is to delineate the determinants of DNA damage susceptibility in genome maintenance and its dysfunction in disease and aging. The immediate goal of the research in this proposal is to determine how DNA damage susceptibility is deregulated in progeria cells and its role in aging phenotypes. Based on published and our preliminary data, we hypothesize that progerin expression alters chromatin architecture and/or chromosomal positioning, rendering cells more susceptible to DNA lesion accumulation and accelerating onset of cellular aging phenotypes. We will test this hypothesis using innovative DNA lesion- mapping techniques that our lab has recently developed, comparative epigenomic analysis, multi-plex chromosomal mapping, and cellular assays associated with DNA damage and senescence. Based on our published and preliminary data, we are ideally positioned to complete the following Specific Aims: Aim 1: Determine the epigenetic architectures that regulate UV susceptibility in progeria cells; and Aim 2: Identify epigenetic interventions that reduce UV susceptibility and cellular aging phenotypes. Expected outcomes from these studies include: high resolution maps of UV susceptibility across the genome of progeria cells; the determination of the chromatin-mediated mechanisms that regulate susceptibility in prematurely aging cells; and identification of epigenetic targets that influence genome stability and aging phenotypes. The rationale for these studies is that once the mechanisms of damage susceptibility are characterized in premature aging cells they can be manipulated to abrogate aging phenotypes initiated by genome instabilities. This research is significant because it reveals a previously unrecognized origin of genome instabilities in HGPS cells, namely increased susceptibility to damage. The research focus of these investigations is also innovative because it will reveal the critical function of the nuclear lamina in protecting against genotoxin exposure. These studies will likely to expand our understanding of typical aging and reveal possible mechanisms for intervention.