Investigator Cancer Center, Mass General Research Institute

Laurel Schwartz Professor of Medicine in the Field of Oncology Harvard Medical School

Kristine and Bob Higgins MGH Research Scholar 2012-2017 Mass General Research Institute, Massachusetts General Hospital

Associate Member Broad Institute

chromatin; chromatin assembly and disassembly; dna repair; epigenetics; genomic instability; histones; immune system; immunoglobulin kappa-chains; longevity; sirtuin 1; sirtuins

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. Energy utilization in cells plays a crucial role in metabolic homeostasis, influencing energy consumption, cell proliferation, stress resistance, and lifespan. Defects in metabolic homeostasis 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 functions as a histone deacetylase to control multiple pathways.

In this context, we have shown that SIRT6 regulates metabolic responses in the cells, and that mice lacking SIRT6 exhibit severe metabolic defects, including fatal hypoglycemia. SIRT6 appears to modulate glucose flux inside the cells, directing glucose away of glycolysis and into the mitochondria for proper ATP production. SIRT6 plays this role by controlling expression of multiple glycolytic genes, acting as a co-repressor of the transcription factor Hif1-alpha.

More recently, we have been focusing on the role of metabolism in cancer, where we believe that SIRT6 plays a critical role in protecting against the glycolytic switch observed in cancer cells (Warburg effect).

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:

• Defining which enzymatic activity is critical for SIRT6 function and to determine the proteins targeted by this activity
• Deciphering how SIRT6 regulates chromatin structure (how its histone deacetylase activity relates to other histone modifications and chromatin remodeling activities)
• Determining whether SIRT6 plays a direct role in regulating cell metabolism in the context of both normal and cancer cells.
• Determining the role of SIRT6 in DNA repair and tumorigenesis using mouse models
• Elucidating the role of histone modifications in DNA repair