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Studies in Saccharomyces cerevisiae and S. pombe have provided important
insights into the process of assembly. A common theme that has emerged is
that heterochromatin assembly is nucleated at specific regulatory sites and
then spreads to nearby sequences. This spread typically requires some phys-
ical coupling of chromatin modifiers and more structural proteins such as
Sir3 and Sir4, and Swi6/HP1 ( Grewal & Elgin, 2002; Moazed, 2001 ).
In S. cerevisiae , site-specific DNA-binding proteins bind to nucleation
sites (silencers) and then recruit to DNA the Sir2/Sir4 complex (Sir-
depending spreading) ( Huang, 2002 ). S. cerevisiae lacks H3K9me3, and
therefore, the silencing occurs through different mechanisms than in fission
yeast. Telomeres and the silent mating-type loci HML and HMR are pack-
aged in silent chromatin that contains the silent information regulator (SIR)
proteins Sir2, Sir3, and Sir4. SIR proteins silence nearby genes at telomeres,
a phenomenon known as the telomere position effect. Silent telomeric chro-
matin is nucleated by the binding of Rap1 (a repressor/activator protein) to
the telomeric CAAA repeats. Rap1 then recruits the SIR protein Sir4 ( Luo,
Vega-Palas, & Grunstein, 2002 ) which in turn recruits Sir2 and Sir3 ( Hoppe
et al., 2002; Rusche, Kirchmaier, & Rine, 2002 ). Silencing at the silent
mating-type loci differs from telomere position effect primarily at this nucle-
ation step: silencers contain binding sites for Rap1, the related Abf1 (an ARS
binding protein), and Orc1 (an origin recognition complex protein). Sir1
seems to bind Orc1 together with a nearby Sir4 to stabilize nucleation of
the SIR complex ( Bose et al., 2004 ). The extending of chromatin, away
from the nucleation site, comprises Sir2, Sir3, Sir4, and nucleosomes
( Strahl-Bolsinger, Hecht, Luo, & Grunstein, 1997 ). Sir4 forms a complex
with Sir2, a NAD-dependent histone deacetylase that deacetylates lysine
16 (K16) on histone H4 ( Liou, Tanny, Kruger, Walz, & Moazed, 2005 ).
Deacetylation of H4K16 allows Sir3 and Sir4 to bind to the H3 and H4 tails
( Carmen, Milne, & Grunstein, 2002; Hecht, Laroche, Strahl-Bolsinger,
Gasser, & Grunstein, 1995 ). These observations led to a model in which
recurrent rounds of deacetylation by the Sir2-Sir4 complex and subsequent
binding of Sir3 and Sir2-Sir4 to deacetylated histone tails propagate silenc-
ing ( Hoppe et al., 2002; Luo et al., 2002; Rusche et al., 2002 ).
The SIR complex in budding yeast seems to be unique: of the SIR pro-
teins, only Sir2 has clear orthologues. In most other eukaryotes, silencing
relies on a common set of related proteins that make up heterochromatin.
As introduced earlier, in S. pombe , specialized repetitive sequences and
RNAi cooperate to initiate heterochromatin formation (stepwise assembly
model). In this case, the shRNAs, generated by RNAi-mediated processing,
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