Genomic instability is a conserved hallmark of eukaryotic aging and increased DNA damage load has been shown to promote both cancer and age-related diseases. We have previously uncovered a potential link between DNA damage and age-related epigenomic changes. Specifically, the histone modifier SIRT1 is redistributed across chromatin in response to DNA damage, moving away from SIRT1-regulated promoters to sites of DNA damage. This reorganization may be critical for efficient DNA repair, but comes at the cost of deregulation of SIRT1 target genes, which mirrors aspects of age-associated transcriptional deregulation. This work led to the more general hypothesis that a DNA damage-induced redistribution of chromatin modifiers (or 'RCM response') may underlie the alterations in gene expression and genomic stability that characterize eukaryotic aging. OBJECTIVE AND RESULTS: To better understand how DNA damage and its repair affect the (epi-)genome over a lifetime, and how these changes impinge on tissue homeostasis, disease progression and mammalian aging, we generated a mouse model that allows for the conditional induction of DNA double-strand breaks (DSB-mice). In this model, the DSB-inducing homing endonuclease I-PpoI is under the control of both Cre-recombinase and a Tamoxifen-activated nuclear translocation domain, and optimal DSB induction requires both Cre and Tamoxifen. We will analyze DSB-mice alone or in the context of established mouse models of age-related diseases, addressing (i) changes in tissue function by histology and biochemical approaches, and (ii) overall chromatin organization using ChIP-seq technology. Preliminary analyses of DSB induction in postmitotic neurons using the CamKII-Cre driver show induction of endonuclease expression. We are presently investigating DSB induction and accumulation in the presence and absence of Tamoxifen. We further generated DSB-mice under the copntrol of a ubiquitous Tamoxifen-inducible Cre, which allows us to investigate the impact of DSBs on a variety of cell lineages, particularly the irradiation sensitive hematopoetic system. We will further be able to isolate mature lymphocytes from these mice and induce DSBs in vitro to study the emerging (epi)genomic changes in primary cells. These compound mouse models may serve as a basis for preventative intervention, either using genetically modified mice or small molecule activators of DNA repair associated chromatin modifiers identified in project 1. As a long-term goal, we will cross these mice to models of age-related degenerative diseases, such as the 3xTg mouse model of Alzheimers disease, and investigate the impact of chronic DNA damage on disease progression. IMPLICATIONS: The potential of DNA damage to affect cell function both through direct DNA alterations and through indirect, epigenetic changes in chromatin structure puts it at a critical position to influence the aging of eukaryotes. A better understanding of how DNA breaks and their repair impinge on tissue homeostasis, cancer and aging is, therefore, critical for the design of targeted intervention, which may be able to prevent or improve many of the negative aspects of DNA break induced chromatin reorganization, given the reversible nature of chromatin modifications.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Kim, Jeongkyu; Sturgill, David; Sebastian, Robin et al. (2018) Replication Stress Shapes a Protective Chromatin Environment across Fragile Genomic Regions. Mol Cell 69:36-47.e7
Kim, Jeongkyu; Sturgill, David; Tran, Andy D et al. (2016) Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability. Nucleic Acids Res 44:e64
Oberdoerffer, Philipp (2015) Stop relaxing: How DNA damage-induced chromatin compaction may affect epigenetic integrity and disease. Mol Cell Oncol 2:e970952
Khurana, Simran; Oberdoerffer, Philipp (2015) Replication Stress: A Lifetime of Epigenetic Change. Genes (Basel) 6:858-77
Singh, Satyendra K; Williams, Carrie A; Klarmann, Kimberly et al. (2013) Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance. J Exp Med 210:987-1001
Shi, Lei; Oberdoerffer, Philipp (2012) Chromatin dynamics in DNA double-strand break repair. Biochim Biophys Acta 1819:811-9
Sinclair, David A; Oberdoerffer, Philipp (2009) The ageing epigenome: damaged beyond repair? Ageing Res Rev 8:189-98