Assistant Professor, Department of Molecular Pharmacology
THE ROLE OF MACRO DOMAIN-MEDIATED REGULATION OF CHROMATIN STRUCTURE AND FUNCTION DURING CANCER AND SENESCENCE
Macro domains are found in several histone variants, chromatin remodelers, and other transcriptional coregulators (e.g. macroH2A, PARP14, CHD1L) with roles in cancer progression, senescence, innate immune responses, and viral pathogenesis. These protein modules function, in part, as ligand binding domains for NAD+-derived poly(ADP-ribose), ADP-ribose, and O-acetyl-ADP-ribose. The ability of macro domains to bind these ligands links the function of macro domain-containing proteins (MDCPs) to NAD+-dependent signaling events catalyzed by NAD+-utilizing enzymes such as PARP-1, PARG and SIRT1. Our laboratory employs a variety of cell-based, genomic and biochemical techniques to explore the role of macro domains, their ligands and the NAD+-utilizing enzymes that produce them in transcriptional regulation.
The histone variant macroH2A1 is an MDCP of particular interest to our group. MacroH2A1 incorporates into nucleosomes found in large chromatin domains that occupy a quarter of the genome in human cells. MacroH2A1 exists as one of two splice variants, macroH2A1.1 which can bind to NAD+-derived ligands, and macroH2A1.2 which cannot associate with these small molecules. Interestingly, while both macroH2A1 variants are present in normal adult cells, macroH2A1.1 splicing is decreased in a variety of human cancers including endometrial, lung, testicular, colon, and bladder cancer. Additionally, macroH2A1.1 can trigger an innate tumor suppressive pathway called oncogene-induced senescence. We are currently exploring the mechanisms that regulate macroH2A1 splicing, the specific roles of each macroH2A variant in transcriptional regulation, and how these processes are perturbed during oncogenesis.
Hussey, K.M., Chen, H., Yang, C., Park, E., Hah, N., Erdjument-Bromage, H., Tempst, P., Gamble, M.J.*, Kraus, W.L.* (2014) “The histone variant macroH2A1 regulates target gene expression in part by recruiting the transcriptional coregulator PELP1.” Mol Cell Biol. 34:2437-49.
Gamble, M.J. (2013) Expanding the functional repertoire of macrodomains. Nat Struct Mol Biol 20:407-8
Zhang, T., Berrocal, J.G., Yao, J., DuMond, M.E., Krishnakumar, R., Ruhl, D.D., Gamble, M.J., and Kraus, W.L. (2012) “Regulation of poly(ADP-ribose) polymerase-1-dependent gene expression through promoter-directed recruitment of a nuclear NAD+ synthase.” J. Biol. Chem. 287:12405-16.
Novikov, L., Klerman, H., Jalloh, A.S., and Gamble, M.J. (2011) “QKI-mediated alternative splicing of the histone variant macroH2A1 regulates cancer cell proliferation.” Mol Cell Biol. 31:4244-4255
Zhang, X., Gamble M.J., Stadler, S., Cherrington, B.D., Causey, C.P., Thompson, P.R., Robertson, M.S., Kraus, W.L., Coonrod, S.A. (2011) “Genome-wide analysis reveals PADI4 Cooperates with ELK-1 to activate c-Fos expression in Breast Cancer Cells.” PLoS Genetics. 7:e1002112.
Gamble, M.J. and Kraus, W.L. (2010) “Multiple facets of the unique histone variant macroH2A: from genomics to cell biology.” Cell Cycle 9:2568-2574.
Gamble, M.J., Frizzell, K.M., Yang, C., Krishnakumar, R., Kraus, W.L. (2010) “The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing.” Genes and Development 24:21-32
Frizzell, K.M., Gamble, M.J., Zhang, T., Berrocal, J.G., Zhang, T., Krishnakumar, R., Cen, Y., Sauve, A.A., and Kraus, W.L. (2009) "Global Analysis of Transcriptional Regulation by Poly(ADP-ribose) Polymerase-1 and Poly(ADP-ribose) Glycohydrolase in MCF-7 Human Breast Cancer Cells." Molecular and Cellular Biology. 284:33926-28
Zhang, T., Berrocal, J.G., Frizzell, K.M., Gamble, M.J., Dumond, M.E., Krishnakumar, R., Yang, T., Sauve, A.A., Kraus, W.L. (2009) “Enzymes in the NAD+ Salvage Pathway Regulate SIRT1 Activity at Target Gene Promoters.” J. Biol Chem. 284:20408-17
Krishnakumar, R.*, Gamble, M.J.*,Frizzell, K.M., Berrocal, J.G., Kininis, M., Kraus, W.L. (2008) Reciprocal binding of PARP-1 and histone H1 at promoters specifies transcriptional outcomes. Science 319:819-21 (* equal contribution)
Gamble, M.J. and Fisher R.P. (2007) SET and PARP1 remove DEK from chromatin to permit access by the transcription machinery. Nat Struct Mol Biol. 14;548-55
Gamble, M.J. and Kraus W.L. (2007) Visualizing the histone code on LSD1. Cell 128:433-4
Larochelle, S., Batliner, J., Gamble, M.J., Barboza, N.M., Kraybill, B.C., Blethrow, J.D., Shokat, K.M., Fisher, R.P.(2006) Dichotomous but stringent substrate selection by the dual-function Cdk7 complex revealed by chemical genetics. Nat Struct Mol Biol 13:55-62
Gamble, M.J., Erdjument-Bromage, H., Tempst, P., Freedman, L.P., Fisher, R.P. (2005) The histone chaperone, TAF-I/SET, is required for activated transcription in vitro of chromatin templates. Mol Cell Biol 25:797-807
Gamble, M.J., Freedman, L.P. (2002) A coactivator code for transcription. Trends Biochem Sci 27: 165-7.
Rachez, C., Gamble, M.J., Chang, C.P., Atkins, G.B., Lazar, M.A. Freedman, L.P. (2000) The DRIP complex and SRC-1/p160 coactivators share similar nuclear receptor binding determinants but constitute functionally distinct complexes. Mol Cell Biol 20:2718-26.
Rachez, C., Lemon, BD., Suldan, Z., Bromleigh, V., Gamble, M., Naar, A.M., Erdjument-Bromage, H., Tempst, P., and Freedman, L.P. (1999) Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature 398:824-8.
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