The role of SIRT6 in DNA damage and neurodegeneration

Aging is characterized by physiological decline of an organism function, leading to disease and death. DNA damage accumulation leads to aging through cellular malfunction, apoptosis and tissue degeneration. Moreover, defects in DNA integrity associate with neurodegeneration, tumorigenesis, immunodeficiencies and aging. Sirtuins are a family of highly conserved protein deacylases/ADP rybosylases that have been linked to the aging process. SIRT6 deficiency leads to a progeroid-like phenotype, and death before 4 weeks of age. In contrast, transgenic mice overexpressing SIRT6 are long lived. We showed that SIRT6 recruits the chromatin remodeler SNF2h to the sites of damage, allowing chromatin relaxation and repair. In the absence of SIRT6 or SNF2H, defects in chromatin remodeling inhibit recruitment of downstream repair factors, such as 53BP1, RPA and BRCA1 causing genomic instability. Remarkably, SIRT6-deficient mice have lower levels of chromatin-associated SNF2H in specific tissues such as the brain. Therefore, we generated brain-specific SIRT6 KO mice to investigate the involvement of SIRT6 in protecting the brain from DNA damage accumulation. Our brain specific SIRT6 KO mouse present impaired behavior with learning and memory defects in mice 3-5 months old. Moreover, we detect signs of premature neurodegeneration by 5 months, together with signs of DNA damage such as ATM and H2AX phosphorylation, and markers of neurodegeneration common in dementias. Our data support the hypothesis that absence of SIRT6 in the brain leads to increase DNA damage accumulation and a premature neurodegenerative phenotype.