The histone deacetylase SIRT6, a critical modulator of metabolism and tumorigenesis

Efficient glucose metabolism is critical for maintaining cel-lular viability. Under normal nutrient and oxygen condi-tions, glucose is converted to pyruvate, entering the mitochondria for oxidative phosphorylation and ATP pro-duction. Under hypoxia or nutrient stress, metabolism is switched to glycolysis, increasing lactate production and reducing mitochondrial respiration, a switch known to play an important role in cancer cells, as defined by Otto Warburg decades ago. Little is known whether chromatin plays a role in carbohydrate flux. The yeast Sir2 protein is an NAD-dependent histone deacetylase that senses the metabolic status of the cell and functions as a chromatin silencer to promote lifespan and genomic stability. Recently, we discovered that the mammalian SIRT6 is a chromatin factor that influences glucose metabolism an

SIRT6 recruits SNF2H to sites of DNA breaks, preventing genomic instability through chromatin remodeling

DNA damage is linked to multiple human diseases, such as cancer, neurodegeneration, and aging. Little is known about the role of chromatin accessibility in DNA repair. Here, we find that the deacetylase sirtuin 6 (SIRT6) is one of the earliest factors recruited to double-strand breaks (DSBs). SIRT6 recruits the chromatin remodeler SNF2H to DSBs and focally deacetylates histone H3K56. Lack of SIRT6 and SNF2H impairs chromatin remodeling, increasing sensitivity to genotoxic damage and recruitment of downstream factors such as 53BP1 and breast cancer 1 (BRCA1). Remarkably, SIRT6-deficient mice exhibit lower levels of chromatin-associated SNF2H in specific tissues, a phenotype accompanied by DNA damage. We demonstrate that SIRT6 is critical for recruitment of a chromatin remodeler as an early step in the DNA damage response, indicating that proper unfolding of chromatin plays a rate-limiting role. We present a unique crosstalk between a histone modifier and a chromatin remodeler, regulating a coordinated response to prevent DNA damage.Fil: Toiber, Deborah. Harvard Medical School; Estados UnidosFil: Erdel, Fabian. Deutsches Krebsforschungszentrum; AlemaniaFil: Bouazoune, Karim. Harvard Medical School; Estados UnidosFil: Silberman, Dafne Magali. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Harvard Medical School; Estados UnidosFil: Zhong, Lei. Harvard Medical School; Estados UnidosFil: Mulligan, Peter. Harvard Medical School; Estados UnidosFil: Sebastián, Carlos. Harvard Medical School; Estados UnidosFil: Cosentino, Claudia. Harvard Medical School; Estados UnidosFil: Martínez Pastor, Bárbara. Harvard Medical School; Estados UnidosFil: Giacosa, Sofia. Harvard Medical School; Estados UnidosFil: D´Urso, Agustina. Harvard Medical School; Estados UnidosFil: Näär, Anders M.. Harvard Medical School; Estados UnidosFil: Kingston, Robert. Harvard Medical School; Estados UnidosFil: Rippe, Karsten. Harvard Medical School; Estados UnidosFil: Mostoslavsky, Raul. Harvard Medical School; Estados Unido