The long-term aim of this project is to delineate the molecular mechanisms which regulate the activity of the mammalian sirtuin, SIRT6, and to explore the therapeutic potential of our observations which suggest that SIRT6 functions as a tumor suppressor gene, and also may act to attenuate age-related pathologies. SIRT6 is one of seven mammalian homologues of the yeast gene, SIR2, which was identified for its ability to regulate lifespan and promote genomic stability. In the absence of SIRT6, SIRT6[-/-] mice develop a premature aging syndrome characterized by genomic instability and shortened lifespan. It is our hypothesis that mammalian life and health-spans are linked to SIRT6 activity, and we propose that understanding the mechanisms which regulate SIRT6 at the cellular level will reveal important insights into mammalian aging and disease. To this end, we will pursue the following specific aims:
Aim 1 : Identify post-translational mechanisms which regulate SIRT6 activity. Here we will identify factors which regulate Sirt6 at the post-translational level. We hae unveiled new evidence which suggests that Sirt6 is phosphorylated in vivo, and that this modification enhances Sirt6 stability, allowing the protein to promote DNA repair and cell survival in response to oxidative stress. We intend to delineate the pathway which results in Sirt6 phosphorylation and its relevance to aging and age-related disease.
Aim2 : Delineate the transcriptional mechanisms that regulate SIRT6 expression. We and other groups have observed that Sirt6 levels are diminished in aging cells. We have observed a similar phenomenon in senescent and non-cycling cells. It appears that a transcriptional mechanism underlies this depletion of Sirt6. We have cloned the promoter of Sirt6 and intend to identify factors which enhance and repress SIRT6 transcription, and how these factors are altered during aging and certain age-related disease processes.
Aim 3 : Examine an emerging role for SIRT6 as a tumor suppressor. Cancer is one of the most abundant age-related diseases. Excitingly, we found that SIRT6 overexpression is selectively cytotoxic to the cancer cell lines and not to the non-transformed cell lines we have examined thus far. We intend to identify the mechanism through which SIRT6 mediates the killing of these cancer cells, examine whether SIRT6 is selectively cytotoxic to additional cancer cell lines, and test, using a mouse model, whether SIRT6 overexpression protects against tumorigenesis in vivo.
The increased aging of the U.S. population has generated a rising interest in the mechanisms which underlie the aging process and the etiology of age-related diseases. In this proposal we outline research related to a gene which has been implicated as a regulator of mammalian life and health-spans. We are optimistic that our research will generate novel insight into the aging process and suggest therapeutic strategies for attenuating age-related diseases.
|Xu, Zhu; Zhang, Lei; Zhang, Wenjun et al. (2015) SIRT6 rescues the age related decline in base excision repair in a PARP1-dependent manner. Cell Cycle 14:269-76|
|Van Meter, Michael; Kashyap, Mehr; Rezazadeh, Sarallah et al. (2014) SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nat Commun 5:5011|
|Van Meter, Michael; Gorbunova, Vera; Seluanov, Andrei (2014) SIRT6: a promising target for cancer prevention and therapy. Adv Exp Med Biol 818:181-96|
|Azpurua, Jorge; Yang, Jiang-Nan; Van Meter, Michael et al. (2013) IGF1R levels in the brain negatively correlate with longevity in 16 rodent species. Aging (Albany NY) 5:304-14|
|Van Meter, Michael; Seluanov, Andrei; Gorbunova, Vera (2012) Â Forever young? Â Exploring the link between rapamycin, longevity and cancer. Cell Cycle 11:4296-7|
|Mao, Zhiyong; Tian, Xiao; Van Meter, Michael et al. (2012) Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence. Proc Natl Acad Sci U S A 109:11800-5|
|Van Meter, Michael; Mao, Zhiyong; Gorbunova, Vera et al. (2011) Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair. Aging (Albany NY) 3:829-35|
|Van Meter, Michael; Mao, Zhiyong; Gorbunova, Vera et al. (2011) SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells. Cell Cycle 10:3153-8|
|Mao, Zhiyong; Hine, Christopher; Tian, Xiao et al. (2011) SIRT6 promotes DNA repair under stress by activating PARP1. Science 332:1443-6|