Sir2 is required for Clr4 to initiate centromeric heterochromatin assembly in fission yeast

Alper, Benjamin J.; Job, Godwin; Yadav, Rajesh K; Shanker, Sreenath; Lowe, Brandon R; Partridge, Janet F.

doi:10.1038/emboj.2013.143

Cited by 60 publications

(78 citation statements)

References 60 publications

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“…3C; Sadaie et al 2004). The histone deacetylases Clr3 and Sir2 function cooperatively with RNAi to establish heterochromatin at pericentric repeats, and H3K9me2 is completely abolished in clr3D dcr1D and sir2D dcr1D cells (Yamada et al 2005;Alper et al 2013;Buscaino et al 2013;Marina et al 2013). The results that poz1D dcr1D cells maintained preexisting heterochromatin but failed to establish heterochromatin de novo suggest that the residual H3K9me in dcr1D cells is necessary for poz1D dcr1D cells to maintain pericentric heterochromatin.…”

Section: Bypassing Rnai Requires Rnai-independent Heterochromatin Assmentioning

confidence: 98%

“…However, even at pericentric regions, H3K9me and Swi6 are still present in RNAi mutants, albeit at lower levels, suggesting the existence of RNAi-independent mechanisms to establish heterochromatin (Sadaie et al 2004). These pathways involve the Clr3 and Sir2 histone deacetylases since H3K9me levels are further reduced from pericentric regions in clr3D dcr1D and sir2D dcr1D cells, although Sir2 seems to function in a separate pathway from Clr3 (Yamada et al 2005;Alper et al 2013;Buscaino et al 2013;Marina et al 2013).…”

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confidence: 98%

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Elimination of shelterin components bypasses RNAi for pericentric heterochromatin assembly

et al. 2013

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The RNAi pathway is required for heterochromatin assembly at repetitive DNA elements in diverse organisms. In fission yeast, loss of RNAi causes pericentric heterochromatin defects, compromising gene silencing and chromosome segregation. Here we show that deletion of telomere shelterin components restores pericentric heterochromatin and its functions in RNAi mutants. We further isolated a separation-of-function mutant of Poz1 and revealed that defective telomere silencing, but not telomere length control, is critical for bypassing RNAi. Further analyses demonstrated that compromising shelterin-mediated heterochromatin assembly in RNAi mutants releases heterochromatin protein Swi6, which is redistributed to pericentric regions through RNAiindependent heterochromatin assembly pathways. Given the high mobility of Swi6 protein and that increased levels of Swi6 facilitates heterochromatin spreading as well as ectopic heterochromatin assembly, our results suggest that constitutive heterochromatin domains use multiple pathways to form high-affinity platforms to restrain Swi6, thus limiting its availability and avoiding promiscuous heterochromatin formation.

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Section: Bypassing Rnai Requires Rnai-independent Heterochromatin Assmentioning

confidence: 98%

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confidence: 98%

Elimination of shelterin components bypasses RNAi for pericentric heterochromatin assembly

et al. 2013

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“…Mif2-myc and other loci (20,21). Thus, if the pericentromeric regions of C. lusitaniae were heterochromatic, a Sir2 ortholog might be enriched in these regions.…”

Section: Myc-cse4mentioning

confidence: 99%

“…In addition, the chromodomain protein HP1 binds methylated H3K9. This type of heterochromatin is best characterized in Schizosaccharomyces pombe, where heterochromatin is established in part through siRNA-presenting Argonaute proteins (19) and is maintained by histone deacetylases, such as Sir2 and Clr3 (20,21).…”

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confidence: 99%

Regional centromeres in the yeast Candida lusitaniae lack pericentromeric heterochromatin

Kapoor

Zhu

Froyd

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Point centromeres are specified by a short consensus sequence that seeds kinetochore formation, whereas regional centromeres lack a conserved sequence and instead are epigenetically inherited. Regional centromeres are generally flanked by heterochromatin that ensures high levels of cohesin and promotes faithful chromosome segregation. However, it is not known whether regional centromeres require pericentromeric heterochromatin. In the yeast Candida lusitaniae, we identified a distinct type of regional centromere that lacks pericentromeric heterochromatin. Centromere locations were determined by ChIP-sequencing of two key centromere proteins, Cse4 and Mif2, and are consistent with bioinformatic predictions. The centromeric DNA sequence was unique for each chromosome and spanned 4-4.5 kbp, consistent with regional epigenetically inherited centromeres. However, unlike other regional centromeres, there was no evidence of pericentromeric heterochromatin in C. lusitaniae. In particular, flanking genes were expressed at a similar level to the rest of the genome, and a URA3 reporter inserted adjacent to a centromere was not repressed. In addition, regions flanking the centromeric core were not associated with hypoacetylated histones or a sirtuin deacetylase that generates heterochromatin in other yeast. Interestingly, the centromeric chromatin had a distinct pattern of histone modifications, being enriched for methylated H3K79 and H3R2 but lacking methylation of H3K4, which is found at other regional centromeres. Thus, not all regional centromeres require flanking heterochromatin.centromere | heterochromatin | Candida | CSE4 | Sir2

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“…As summarized in Figure 6, our results suggest that under conditions for which a compromised interaction between microtubules and the kinetochore leads to SAC activation, mitotic arrest, and cell death, the presence of additional mutations that alter the epigenetic state of centromeric chromatin can correct the dis phenotype and promote cell survival. Given that Clr6, Clr3, and Sir2 play key roles in heterochromatin assembly (Pidoux and Allshire 2005;Alper et al 2013;Buscaino et al 2013), we interpret these results to suggest that alterations in centromeric chromatin may create a permissive chromatin landscape that allows interactions of microtubules with the kinetochore such that the SAC is silenced and sister chromatids separate. Because Swi6 is thought to recruit cohesin to centromeres (Partridge et al 2002), the absence of swi6 may lead to loss of cohesion and further alterations in centromere architecture that favor silencing of the SAC, thereby promoting sister-chromatid separation.…”

Section: Discussionmentioning

confidence: 90%

Escape from Mitotic Arrest: An Unexpected Connection Between Microtubule Dynamics and Epigenetic Regulation of Centromeric Chromatin in Schizosaccharomyces pombe

George

Walworth

2015

Genetics

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Accurate chromosome segregation is necessary to ensure genomic integrity. Segregation depends on the proper functioning of the centromere, kinetochore, and mitotic spindle microtubules and is monitored by the spindle assembly checkpoint (SAC). In the fission yeast Schizosaccharomyces pombe, defects in Dis1, a microtubule-associated protein that influences microtubule dynamics, lead to mitotic arrest as a result of an active SAC and consequent failure to grow at low temperature. In a mutant dis1 background (dis1-288), loss of function of Msc1, a fission yeast homolog of the KDM5 family of proteins, suppresses the growth defect and promotes normal mitosis. Genetic analysis implicates a histone deacetylase (HDAC)-linked pathway in suppression because HDAC mutants clr6-1, clr3D, and sir2D, though not hos2D, also promote normal mitosis in the dis1-288 mutant. Suppression of the dis phenotype through loss of msc1 function requires the spindle checkpoint protein Mad2 and is limited by the presence of the heterochromatin-associated HP1 protein homolog Swi6. We speculate that alterations in histone acetylation promote a centromeric chromatin environment that compensates for compromised dis1 function by allowing for successful kinetochore-microtubule interactions that can satisfy the SAC. In cells arrested in mitosis by mutation of dis1, loss of function of epigenetic determinants such as Msc1 or specific HDACs can promote cell survival. Because the KDM5 family of proteins has been implicated in human cancers, an appreciation of the potential role of this family of proteins in chromosome segregation is warranted. KEYWORDS Msc1; lysine demethylase KDM5; histone deacetylase (HDAC); Rb; PLU-1; RBP2; trichostatin; thiabendazole; Mad2; Dis1 (XMAP215, TOG1); Swi6 (HP1 homolog) A CCURATE chromosome segregation relies on precise assembly of the multiprotein kinetochore complex, which mediates the link between chromosomes and the mitotic spindle (Przewloka and Glover 2009). The histone H3 variant CENP-A, along with epigenetic marks on canonical histones, defines centromeric chromatin, which forms the template for kinetochore assembly (Allshire and Karpen 2008;Verdaasdonk and Bloom 2011). Kinetochores serve as the site of spindle microtubule attachment (Santaguida and Musacchio 2009) and, along with the centromere, translate microtubule attachment status to mediate force balance, tension sensing, and spindle checkpoint control (Bloom 2014). When associations between chromosomes and the spindle are incorrect, the spindle assembly checkpoint (SAC) delays progression through mitosis by preventing the onset of anaphase (Musacchio and Salmon 2007;Foley and Kapoor 2013).Fission yeast centromeric chromatin (Allshire and Ekwall 2015) consists of a central core (cnt) and internal inverted repeats (imr), defined by the presence of CENP-A and methylated histone H3 K4 chromatin, flanked by heterochromatic outer repeats (otr) marked by methylated histone H3 K9 (Partridge et al. 2000;Takahashi et al. 2000;Kniola et al. 2001). The consti...

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Sir2 is required for Clr4 to initiate centromeric heterochromatin assembly in fission yeast

Cited by 60 publications

References 60 publications

Elimination of shelterin components bypasses RNAi for pericentric heterochromatin assembly

Elimination of shelterin components bypasses RNAi for pericentric heterochromatin assembly

Regional centromeres in the yeast Candida lusitaniae lack pericentromeric heterochromatin

Escape from Mitotic Arrest: An Unexpected Connection Between Microtubule Dynamics and Epigenetic Regulation of Centromeric Chromatin in Schizosaccharomyces pombe

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