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Mol. Cell. Biol. doi:10.1128/MCB.01641-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Swapping the gene-specific and regional silencing specificities of the Hst1 and Sir2 histone deacetylases

Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, New Jersey, 08854; Department of Pharmacology, University of Medicine and Dentistry New Jersey, Piscataway, New Jersey, 08854

^* To whom correspondence should be addressed. Email: vershon{at}waksman.rutgers.edu.

	Abstract

Sir2 and Hst1 are NAD⁺-dependent histone deacetylaces of budding yeast that are related by strong sequence similarity. Nevertheless, the two proteins promote two mechanistically distinct forms of gene repression. Hst1 interacts with Rfm1 and Sum1 to repress transcription of specific middle-sporulation genes. Sir2 interacts with Sir3 and Sir4 to silence genes contained within the silent mating-type loci and telomere chromosomal regions. To identify the determinants of gene-specific versus regional repression we created a series of Hst1::Sir2 hybrids. Our analysis yielded two dual specificity chimeras that were able to perform both regional and gene-specific repression. Regional silencing by the chimeras required Sir3 and Sir4, whereas gene-specific repression required Rfm1 and Sum1. Our findings demonstrate that the non-conserved N-terminal region and two amino acids within the enzymatic core domain account for cofactor specificity and proper targeting of these proteins. These results suggest that the differences in the silencing and repression functions of Sir2 and Hst1 may not be due to differences in enzymatic activities of the proteins but rather may be a result of distinct cofactor specificities.