Raul Mostoslavsky
Department of Medicine
Massachusetts General Hospital
Simches Research Building, CPZN 4208, 4th Floor
185 Cambridge Street
Boston, MA 02114
Tel: (617) 643-3146
Fax: (617) 643-3170
Email: rmostoslavsky@mgh.harvard.edu
Web Page: The Mostoslavsky Lab Page
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, extending in this way the yeast lifespan. We have found that one of the mammalian Sir2 homologues, SIRT6, binds to chromatin and regulates DNA repair through the Base Excision Repair pathway that removes oxidated and alkylated DNA bases. In addition, we have shown that SIRT6 regulates metabolic responses in the cells, and that mice lacking SIRT6 exhibit severe metabolic defects, including hypoglycemia and hypoinsulinemia.
Our 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.
Current projects
- Defining which enzymatic activity is critical for SIRT6 function (SIRT6 can function as an ADP-ribosyl transferase or as a deacetylase in vitro) and to determine the proteins targeted by this activity
- Deciphering how SIRT6 regulates chromatin structure
- Determining whether SIRT6 plays a direct role in regulating cell metabolism, insulin signaling, and lifespan.
- Determining the role of SIRT6 in DNA repair and tumorigenesis using mouse models
- Elucidating the role of histone modifications in DNA repair
References:
- Finkel, T., Deng, C-H., and Mostoslavsky, R. (2009). Recent Progress in the biology and physiology of sirtuins. Nature 460, 587-591.
- Zhong, L., D’Urso, A., Toiber, D., Sebastian, C., Henry, R.E., Vadysirisack, D.D., Guimaraes, A., Marinelli, B., Wikstrom, J.D., Nir, T., Clish, C.B., Vaitheesvaran, Iliopoulos, O., B., Kurland, I., Dor, Y., Weissleder, R., Shirihai, O.S., Ellisen, L., Espinosa, J.M., and Mostoslavsky, R. (2010). The histone deacetylase SIRT6 regulates glucose homeostasis via Hif1a. Cell, 140, 280-293.
- Mostoslavsky, R., Chua, K.F, Lombard, D.L., Pang, W.W, Fischer, M.R., Gellon, L., Liu, P., Mostoslavsky, G., Franco, S., Murphy, M.M., Mills, K.D., Patel, P., Hsu, J., Hong, A.L., Ford, E., Cheng, H-L., Kennedy, C., Nunez, N., Bronson, R., Frendewey, D., Auerbach, W., Valenzuela, D., Karow, M., Hottiger, M.O., Hursting, S., Barrett, J.C., Guarente, L., Mulligan, R., Demple, B., Yancopolous, G.D., and Alt, F.W. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 2004, 124:315-329.
- Mostoslavsky, R., Singh, N., Tenzen, T., Goldmit, M., Gabay, C., Elizur, S., Qi, P., Reubinoff B.E., Chess, A., Cedar, H., and Bergman, Y. Asynchronous replication and allelic exclusion in the immune system. Nature 2001, 414:221-225.
BBS webpage updated 12/02/2009