The long-term goal of this project is to define the molecular mechanisms which regulate the activity of the mammalian sirtuin, SIRT6, especially in the context of genome stability. Additionally, the studies outlined in this proposal will delineate the relevance of these regulatory controls in regards to aging and the onset of age- related disease. SIRT6 has emerged as a critical regulator of multiple pathways related to aging, including DNA repair, telomere maintenance, tumorigenesis, inflammation and glycolysis. Moreover, it has been demonstrated that SIRT6 overexpression extends the lifespan of mice. Despite the overwhelming evidence that SIRT6 operates at the crux of multiple pathways related to aging, very little is known about the upstream regulatory mechanisms which control the activity of SIRT6 and allow it to regulate such a diverse array of cellular processes. In this application we propose to identify the regulatory pathways that control the activity of SIRT6; in particular, we will focus on understanding the mechanisms that regulate the activity of SIRT6 in the context of genome stability. Recent studies by our laboratory demonstrated that SIRT6 is an upstream regulator of DNA double strand break (DSB) repair. We showed that SIRT6 stimulates both pathways of DSB repair under oxidative stress. Our unpublished preliminary data shows that SIRT6 is phosphorylated by JNK1/2 in response to oxidative stress on amino acid S10 and that this phosphorylation is required for the stimulation of DSB repair. We have also shown that, in addition to controlling DSB repair, SIRT6 maintains genome stability by repressing transposable elements, and that oxidative stress causes re-localization of SIRT6 from the promoters of transposable elements to the sites of newly formed DNA breaks. Thus, we are ideally positioned to conduct further mechanistic studies of SIRT6 regulation in the context of genome stability. As such, we will pursue the following specific aims: (1) identify the mechanisms which regulate the ability of SIRT6 to stimulate DNA repair in response to oxidative stress; (2) identify the mechanisms which regulate the ability of SIRT6 to suppress expression of LINE-1 retrotransposons; and (3) determine the role of SIRT6 phosphorylation in genome stability and longevity by constructing mouse models with mutations in the SIRT6 phosphorylation sites. The proposed research will provide novel and important insights into the regulatory mechanisms, which govern SIRT6 activity as well as delineate new pathways regulated by SIRT6 which are relevant to genome stability and aging. As such, we expect that these experiments will reveal critical, new information about the aging process, and will help to develop novel strategies for treating age-related diseases, in particular diseases of genome instability such as cancer.

Public Health Relevance

The increased aging of the U.S. population has generated a significant interest in the mechanisms which underlie the aging process and the etiology of age-related diseases. In this proposal we outline research related to one gene, SIRT6, which has been implicated as a regulator of mammalian life and health-spans. Our research focuses on identifying the molecular mechanisms that regulate SIRT6 and understanding how these mechanisms can be modulated for therapeutic benefit. We are optimistic that our research will provide novel insight into the aging process and lead to therapeutic strategies designed to attenuate age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG046320-05
Application #
9435067
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
2014-04-15
Project End
2019-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Rochester
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Valenzano, Dario Riccardo; Aboobaker, Aziz; Seluanov, Andrei et al. (2017) Non-canonical aging model systems and why we need them. EMBO J 36:959-963
Tian, Xiao; Seluanov, Andrei; Gorbunova, Vera (2017) Molecular Mechanisms Determining Lifespan in Short- and Long-Lived Species. Trends Endocrinol Metab 28:722-734
Moskalev, Alexey; Anisimov, Vladimir; Aliper, Aleksander et al. (2017) A review of the biomedical innovations for healthy longevity. Aging (Albany NY) 9:7-25
Tan, Li; Ke, Zhonghe; Tombline, Gregory et al. (2017) Naked Mole Rat Cells Have a Stable Epigenome that Resists iPSC Reprogramming. Stem Cell Reports 9:1721-1734
Ke, Zhonghe; Mallik, Pramit; Johnson, Adam B et al. (2017) Translation fidelity coevolves with longevity. Aging Cell 16:988-993
Gorbunova, Vera; Seluanov, Andrei (2016) DNA double strand break repair, aging and the chromatin connection. Mutat Res 788:2-6
Dokukin, Maxim; Ablaeva, Yulija; Kalaparthi, Vivekanand et al. (2016) Pericellular Brush and Mechanics of Guinea Pig Fibroblast Cells Studied with AFM. Biophys J 111:236-46
Patrick, Alison; Seluanov, Michael; Hwang, Chaewon et al. (2016) Sensitivity of primary fibroblasts in culture to atmospheric oxygen does not correlate with species lifespan. Aging (Albany NY) 8:841-7
Hewitt, Graeme; Carroll, Bernadette; Sarallah, Rezazadeh et al. (2016) SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair. Autophagy 12:1917-1930
Gorbunova, Vera; Rezazadeh, Sarallah; Seluanov, Andrei (2016) Dangerous Entrapment for NRF2. Cell 165:1312-1313

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