Marc Gartenberg Professor UMDNJ-RWJMS Department of Pharmacology RWJMS Research Building Room 284 683 Hoes Lane West Piscataway. NJ 08854 (732) 235-5800 FAX - 235-4780 gartenbe@umdnj.edu

Chromatin structure. gene regulation. and epigenetic inheritance in yeast

Chromatin Structure and Function - Large regions of eukaryotic chromosomes are transcriptionally repressed due to packaging of DNA in heterochromatin. a structure that is heritably propagated from one mitotic cycle to the next. Other chromosomal regions are transcriptionally active for brief periods during development and then repressed permanently. Because inappropriate expression of down-regulated genes often leads to cancers and other genetic diseases. we are interested in how large chromosomal domains are transcriptionally inactivated.

In yeast. a heterochromatin-like structure. termed silent chromatin. represses genes at telomeres and the silent mating loci. In both cases. repression requires cis-acting regulatory sequences and a set of non-histone chromatin components. We are studying silent chromatin to determine how heterochromatic repression is established. maintained. and ultimately propagated from one generation to the next. To this end. we are developing a host of novel approaches to address the following issues: 1) the role of DNA replication in establishing silent chromatin; 2) the role of cis-acting elements in maintaining the repressive structure; 3) the relationship between nuclear localization and transcriptional repression; 4) the composition and structure of biochemically isolated silent chromatin fragments.

Repair of DNA damaged by proteins - DNA topoisomerases catalyze DNA strand breakage and rejoining reactions to facilitate nearly all DNA based events. including transcription. replication. recombination and chromosome segregation. An obligatory intermediate of the topoisomerase reaction involves formation of a covalent linkage between the enzyme and DNA. Numerous anti-cancer agents act by trapping this intermediate. thereby creating DNA lesions with a protein attached. Cellular processing of protein-linked DNA lesions is likely to mitigate the efficacy of these topoisomerase inhibitors. To learn how cells deal with this type of damage. we have developed a system to induce protein-linked DNA damage at a specific site in vivo. Biochemical and genetic methods are being employed to study the fate of the DNA and protein constituents at these DNA damage sites.

Selected Publications

Valenzuela L, Dhillon N, Dubey RN, Gartenberg MR, Kamakaka RT. (2008) Long-range communication between the silencers of HMR. Mol Cell Biol. 28(6):1924-35.

Schober H, Kalck V, Vega-Palas MA, Van Houwe G, Sage D, Unser M, Gartenberg MR, Gasser SM. (2008) Controlled exchange of chromosomal arms reveals principles driving telomere interactions in yeast. Genome Res. 18(2):261-71.

Dubey RN, Gartenberg MR. (2007) A tDNA establishes cohesion of a neighboring silent chromatin domain. Genes Dev. 21(17):2150-60.

Mead J, McCord R, Youngster L, Sharma M, Gartenberg MR, Vershon AK. (2007) Swapping the gene-specific and regional silencing specificities of the Hst1 and Sir2 histone deacetylases. Mol Cell Biol. 27(7):2466-75.

Chang CR. Wu CS. Hom Y. Gartenberg MR. (2005) Targeting of cohesin by transcriptionally silent chromatin. Genes Dev. 19(24):3031-42.

Taddei A. Gartenberg MR. Neumann FR. Hediger F. Gasser SM.(2005) Multiple pathways tether telomeres and silent chromatin at the nuclear periphery: functional implications for sir-mediated repression. Novartis Found Symp. 264:140-56; discussion 156-65. 227-30.

Gartenberg MR. Neumann FR. Laroche T. Blaszczyk M. Gasser SM. (2004) Sir-mediated repression can occur independently of chromosomal and subnuclear contexts. Cell. 119(7):955-67.

Andrulis. E.A.. Zappulla. D.C.. Ansari. A.I.. Perrod. S.. Laiosa. C.V.. Gartenberg. M.R.. * and Sternglanz. R.* (2002). Esc1. a nuclear periphery protein required for Sir4-based plasmid anchoring and partitioning. Mol. Cell. Biol. 22. 8292-8301. *Cocorresponding Authors

Li. Y.-C.. Cheng. T.H.. and Gartenberg. M.R. (2001). Establishment of transcriptional silencing in the absence of DNA replication. Science 291:650-653.

Gartenberg. M.R. (2000). The Sir proteins of Saccharomyces cerevisiae: mediators of transcriptional silencing and much more. Curr. Opin. Microbiol. 3:132-137.

Cheng. T.-H. and Gartenberg. M. R. (2000). Maintenance of yeast heterochromatin is a dynamic process that requires silencers continuously. Genes & Dev. 14:452-463.