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Vol. 10, Issue 9, 3045-3059, September 1999
*Department of Molecular, Cellular, and Developmental Biology,
Porter Biosciences, University of Colorado, Boulder, Colorado
80309-0347; Silencing is a universal form of transcriptional regulation in
which regions of the genome are reversibly inactivated by changes in
chromatin structure. Sir2 (Silent Information Regulator) protein is
unique among the silencing factors in Saccharomyces
cerevisiae because it silences the rDNA as well as the silent
mating-type loci and telomeres. Discovery of a gene family of
Homologues of Sir Two (HSTs) in organisms
from bacteria to humans suggests that SIR2's silencing
mechanism might be conserved. The Sir2 and Hst proteins share a core
domain, which includes two diagnostic sequence motifs of unknown
function as well as four cysteines of a putative zinc finger. We
demonstrate by mutational analyses that the conserved core and each of
its motifs are essential for Sir2p silencing. Chimeras between Sir2p
and a human Sir2 homologue (hSir2Ap) indicate that this human
protein's core can substitute for that of Sir2p, implicating the core
as a silencing domain. Immunofluorescence studies reveal partially
disrupted localization, accounting for the yeast-human chimeras'
ability to function at only a subset of Sir2p's target loci. Together,
these results support a model for the involvement of distinct
Sir2p-containing complexes in HM/telomeric and rDNA
silencing and that HST family members, including the
widely expressed hSir2A, may perform evolutionarily
conserved functions.
Department of Molecular Biology and
Pharmacology, Washington University School of Medicine, St. Louis,
Missouri 63110; and §Department of Molecular Biology and
Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205
Present address: Department of Biology,
Pacific Hall 0347, 9500 Gilman Drive, University of California, San
Diego, La Jolla, CA 92093-0347.
Corresponding Author: E-mail address:
lpillus{at}biomail.ucsd.edu.
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