Nonhomologous end joining (NHEJ) is a pathway that repairs DMA double-strand breaks (DSBs) and is essential for assuring longevity. Ku80 is critical for NHEJ and Ku80-mutant mice and cells are hypersensitive to agents that cause DMA DSBs. These mutant mice also exhibit premature signs of normal aging. Importantly, Ku80-mutant mice only start showing these signs at about 40 weeks while control mice start showing the same signs about 40 weeks later. Our goal is to discover the underling factors that cause this aging phenotype and to relate these discoveries to human aging. We will test two hypotheses. 1) Early aging is caused by an accumulation of chromosomal aberrations that impair cell function. This is possible since Ku80-mutant mice exhibit an early onset of chromosomal aberrations that are also seen in controls, but at a later age. Even though chromosomal aberrations are known to increase cancer, Ku80-mutant mice curiously exhibit low cancer levels suggesting the underling factors that cause early aging also decrease cancer. Second, we will test if inefficiently repaired DMA causes persistent activation of tumor suppressor pathways that lead to early aging and decreased cancer. To support this possibility Ku80-deletion ameliorates tumor burden in cancer-prone mice that have normal DMA damage responses while exacerbating tumors in cancer-prone mice with defective DMA damage respones. We propose three aims to address these hypotheses that are tightly integrated with Core B and Projects 1, 2, 3 and 5.
Aim 1 addresses the impact p16 has on Ku80-mutant mice. p16 is a tumor suppressor and aging biomarker. We will analyze Ku80- mutant mice that lack p16.
Aim 2 addresses the possibility that DNA-PKcs is toxic in Ku80-mutant mice. DNA-PKcs is a component of NHEJ. Strangely, DNA-PKcs-mutant mice do not show the same severe aging phenotype as Ku80-mutant mice suggesting that defective NHEJ alone does not cause early aging. Thus, it is possible that DNA-PKcs, in the absecence of Ku80 forms nonproductive intermediates or induces cellular responses that contribute to the aging phenotpe.
Aim 3 addresses the role human NHEJ-related gene-SNP variants have on genome maintenance and aging. We will use a novel high throughput knockin system developed in our lab to compare function of the gene variants and determine if they contribute to aging and longevity. These studies will be facilitated by a novel DNA mutation reporter ideal for detecting a wide range of mutations and evaluating DSB repair pathways in proliferating cells. Completion of these aims will help evaluate the role Ku80 and DNA damage responses have on aging and cancer in mice and humans.
These studies will help us understand the role DNA damage responses play in longevity and aging and the relationship aging has to cancer in mice and humans. We will study this relationship in mice and then apply it to humans by analyzing DNA repair gene SNP variants that associate with longevity in humans. Thus, these studies will elucidate the causes of aging by analyzing longevity assurance mechanisms.
|Lau, Cia-Hin; Suh, Yousin (2016) Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging-Related Disease. Gerontology :|
|Andriani, Grasiella A; Faggioli, Francesca; Baker, Darren et al. (2016) Whole chromosome aneuploidy in the brain of Bub1bH/H and Ercc1-/Î”7 mice. Hum Mol Genet 25:755-65|
|Sepe, Sara; Milanese, Chiara; Gabriels, Sylvia et al. (2016) Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease. Cell Rep 15:1866-75|
|Kruiswijk, F; Hasenfuss, S C; Sivapatham, R et al. (2016) Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling. Oncogene 35:2166-77|
|Ryu, Seungjin; Atzmon, Gil; Barzilai, Nir et al. (2016) Genetic landscape of APOE in human longevity revealed by high-throughput sequencing. Mech Ageing Dev 155:7-9|
|Kato, Kaori; Zweig, Richard; Schechter, Clyde B et al. (2016) Positive attitude toward life, emotional expression, self-rated health, and depressive symptoms among centenarians and near-centenarians. Aging Ment Health 20:930-9|
|Quispe-Tintaya, Wilber; Gorbacheva, Tatyana; Lee, Moonsook et al. (2016) Quantitative detection of low-abundance somatic structural variants in normal cells by high-throughput sequencing. Nat Methods 13:584-6|
|Gravina, Silvia; Dong, Xiao; Yu, Bo et al. (2016) Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome. Genome Biol 17:150|
|Vermeij, Wilbert P; Hoeijmakers, Jan H J; Pothof, Joris (2016) Genome Integrity in Aging: Human Syndromes, Mouse Models, and Therapeutic Options. Annu Rev Pharmacol Toxicol 56:427-45|
|Vijg, Jan; Kennedy, Brian K (2016) The Essence of Aging. Gerontology 62:381-5|
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