Cells need to accurately maintain their nuclear DNA in order to function properly. Indeed, defects in DNA integrity are associated with cancer, aging, and immunodeficiency. Therefore, numerous DNA repair systems in mammalian cells function to endow us with long and relatively tumor-free lives. The DNA and the histones are arranged in the nucleus in a highly condensed structure known as chromatin. Cellular processes that unwind the double helix, such as transcription, replication and DNA repair, have to overcome this natural barrier to DNA accessibility.
Multicellular organisms also need to control their use of cellular energy stores. The insulin signaling (IS) pathway plays a crucial role in metabolic homeostasis, influencing energy consumption, cell proliferation, stress resistance, and lifespan. Defective insulin signaling causes numerous diseases ranging from diabetes to an increased tendency to develop tumors. For cells to respond appropriately to changes in energy status or to DNA damage, there is likely to be a close coupling of DNA repair, chromatin remodelling and metabolic pathways.
Our lab is interested in understanding the influence of chromatin on DNA repair, and the relationship between the DNA damage response and the metabolic adaptation of cells. We focus on the study of a group of proteins called SIRTs, the mammalian homologues of the yeast Sir2. Sir2 is a chromatin silencer that functions as an NAD-dependent histone deacetylase to inhibit DNA transcription and recombination. We have found that one of the mammalian Sir2 homologues, SIRT6, binds to chromatin and regulates DNA repair and gene transcription. In addition, we have shown that SIRT6 regulates metabolic responses in cells, and mice lacking SIRT6 exhibit severe metabolic defects, including a fatal hypoglycemia. SIRT6 appears to modulate glucose flux inside the cells, directing glucose away of glycolysis and into mitochondrial respiration. In this context, SIRT6 appears to play a critical role in protecting against glycolytic-dependent tumorigenesis.
Our current studies are directed at determining how the DNA repair and metabolic functions of SIRT6 may be related to each other. We use a number of experimental systems, including biochemical and biological approaches, as well as genetically engineered mouse models.
Specific projects include:
- Deciphering how SIRT6 regulates chromatin structure, in particular its role in transcriptional elongation and DNA repair
- Determining whether SIRT6 plays a direct role in regulating cell metabolism both in normal and cancer cells
- Determining the role of SIRT6 in DNA repair and tumorigenesis using mouse models
- Elucidating the role of histone modifications and novel chromatin factors in DNA repair
- Understand the crosstalk between epigenetics and metabolism, specifically the role of metabolites availability in determining chromatin modifications and viceversa.
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