Gene Ontology annotation through association of InterPro records with GO terms
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic Gene Ontology annotation based on Rhea mapping
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Regulation of chromatin structure by site-specific histone H3 methyltransferases.
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SUV39H1/Suv39h1, mammalian homologs of S. pombe clr4, are histone H3-specific methyltransferases that selectively methylate H3K9 via the SET domain plus adjacent cysteine-rich regions.
"encode histone H3-specific methyltransferases that selectively methylate lysine 9 of the amino terminus of histone H3 in vitro. We mapped the catalytic motif to the evolutionarily conserved SET domain, which requires adjacent cysteine-rich regions to confer histone methyltransferase activity."
Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly.
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Clr4 preferentially methylates H3K9 at heterochromatic regions in vivo, and both the chromo- and SET domains are required; H3K9me is needed for Swi6 localization.
"lysine 9 of histone H3 (H3 Lys9) is preferentially methylated by the Clr4 protein at heterochromatin-associated regions in fission yeast. Both the conserved chromo- and SET domains of Clr4 are required for H3 Lys9 methylation in vivo."
RNA-dependent RNA polymerase is an essential component of a self-enforcing loop coupling heterochromatin assembly to siRNA production.
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A self-enforcing RNAi loop couples siRNA production to heterochromatin assembly; RITS/Rdp1 localization at centromeric repeats depends on Clr4 and Swi6.
"its localization at centromeric repeats depends on components of RITS and Dicer as well as heterochromatin assembly factors including Clr4/Suv39h and Swi6/HP1 proteins"
A Rik1-associated, cullin-dependent E3 ubiquitin ligase is essential for heterochromatin formation.
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A Rik1-/Clr4-associated cullin-dependent E3 ubiquitin ligase (with Raf1, Raf2, Pcu4, Pip1) is essential for H3K9 methylation and heterochromatin formation.
"subunits of a cullin-dependent E3 ubiquitin ligase are associated with Rik1 and Clr4, and Rik1-TAP preparations exhibit robust E3 ubiquitin ligase activity."
Ubiquitin ligase component Cul4 associates with Clr4 histone methyltransferase to assemble heterochromatin.
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Clr4 directly associates with the cullin Cul4/Pcu4; Cul4 is required for Clr4 localization, H3K9 methylation, Swi6 recruitment and silencing.
"We show that Clr4 associates with Cul4, a cullin family protein that serves as a scaffold for assembling ubiquitin ligases. Mutations in Cul4 result in defective localization of Clr4 and loss of silencing at heterochromatic loci."
ORFeome cloning and global analysis of protein localization in the fission yeast Schizosaccharomyces pombe.
RNAi-dependent and -independent RNA turnover mechanisms contribute to heterochromatic gene silencing.
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RNAi and RNA turnover (Cid14/TRAMP-like) cooperate in heterochromatic gene silencing at centromeric repeats.
"the RNAi pathway is required for heterochromatin-dependent silencing of transgene insertions at centromeric repeats"
Roles of the Clr4 methyltransferase complex in nucleation, spreading and maintenance of heterochromatin.
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ClrC nucleates and spreads heterochromatin; the Clr4 chromodomain binds H3K9me to enable spreading, and Clr4's write/read of H3K9me underlies maintenance.
"the chromodomain of Clr4 binds specifically to H3K9me that is essential for the spreading of heterochromatin... the ability of Clr4 to both 'write' and 'read' H3K9me facilitates heterochromatin maintenance through successive cell divisions."
Phosphorylation of Swi6/HP1 regulates transcriptional gene silencing at heterochromatin.
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CK2-dependent Swi6 phosphorylation controls transcriptional gene silencing downstream of Clr4-mediated heterochromatin.
"CK2-dependent Swi6 phosphorylation specifically controls TGS in heterochromatin."
Stc1: a critical link between RNAi and chromatin modification required for heterochromatin integrity.
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Stc1 bridges the RNAi effector Ago1 to the CLRC complex, recruiting Clr4 to promote H3K9 methylation.
"This leads to recruitment of the CLRC complex, including the histone methyltransferase Clr4, promoting H3K9 methylation and heterochromatin formation."
Clr4/Suv39 and RNA quality control factors cooperate to trigger RNAi and suppress antisense RNA.
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Clr4 interacts with Mlo3 (and methylates it); loss of Clr4 impairs RITS-Mlo3 interaction required for centromeric siRNA production and antisense suppression.
"Clr4 and the RNAi effector RITS (RNA-induced transcriptional silencing) interact with Mlo3, a protein related to mRNA quality control and export factors. Loss of Clr4 impairs RITS interaction with Mlo3, which is required for centromeric siRNA production and antisense suppression."
RNA elimination machinery targeting meiotic mRNAs promotes facultative heterochromatin formation.
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Facultative heterochromatin islands form at meiotic genes via RNA elimination factors (Mmi1/Red1) that interact with Clr4/SUV39h.
"RNA elimination machinery is enriched at meiotic loci and interacts with Clr4/SUV39h, a methyltransferase involved in heterochromatin assembly."
Intrinsic nucleic acid-binding activity of Chp1 chromodomain is required for heterochromatic gene silencing.
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This study characterizes intrinsic nucleic-acid binding by fission-yeast chromodomains. While the title emphasizes Chp1, the paper also assays the Clr4 chromodomain and reports that Clr4 (the SUV39H homolog) binds nucleic acid via its chromodomain, supporting the PomBase dsDNA/ssDNA/ssRNA-binding IDA annotations to clr4 (a non-core ancillary property of the chromodomain).
"Intrinsic nucleic acid-binding activity of Chp1 chromodomain is required for heterochromatic gene silencing."
Elimination of shelterin components bypasses RNAi for pericentric heterochromatin assembly.
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Deletion of telomere shelterin components restores pericentric heterochromatin in RNAi mutants by releasing Swi6 for RNAi-independent assembly; informs subtelomeric heterochromatin formation by Clr4.
"deletion of telomere shelterin components restores pericentric heterochromatin and its functions in RNAi mutants"
CRL4-like Clr4 complex in Schizosaccharomyces pombe depends on an exposed surface of Dos1 for heterochromatin silencing.
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Clr4 is the only H3K9 methyltransferase in S. pombe and a subunit of the CRL4-like CLRC complex (Cul4, Pip1, Rik1, Dos1); H3K9me deposition depends on the RNAi pathway.
"Cryptic loci regulator 4 (Clr4), the only known H3K9 methyltransferase in this organism, is a subunit of the Clr4 methyltransferase complex (CLRC), whose composition is reminiscent of a CRL4 type cullin-RING ubiquitin ligase"
Clr4 specificity and catalytic activity beyond H3K9 methylation.
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Clr4 introduces H3K9 di-/tri-methylation and also methylates non-histone substrates including Mlo3 and additional target sites.
"The enzyme introduces histone 3 lysine 9 (H3K9) di- and tri-methylation, a central heterochromatic histone modification, and later it was also found to methylate the Mlo3 protein, which has a role in heterochromatin formation as well."
Automethylation-induced conformational switch in Clr4 (Suv39h) maintains epigenetic stability.
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An internal autoinhibitory loop blocks the H3K9 substrate pocket; automethylation of K455 (and K472) triggers a conformational switch that activates Clr4 and prevents aberrant heterochromatin spreading.
"an internal loop in Clr4 inhibits the catalytic activity of this enzyme by blocking the histone H3K9 substrate-binding pocket, and that automethylation of specific lysines in this loop promotes a conformational switch that enhances the H3K9me activity of Clr4."
Disordered region of H3K9 methyltransferase Clr4 binds the nucleosome and contributes to its activity.
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The Clr4 chromodomain binds the H3K9me3 tail and, together with the disordered linker, binds the nucleosome core to contribute to H3K9 methylation in vitro and in vivo.
"the Clr4 chromodomain binds the H3K9me3 tail and that both, the chromodomain and the disordered region connecting the chromodomain and the SET domain, bind the nucleosome core."
H3K14 ubiquitylation promotes H3K9 methylation for heterochromatin assembly.
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CLRC (Clr4 + Cul4) ubiquitylates H3K14, and H3K14ub promotes Clr4 H3K9 methylation for heterochromatin assembly.
"H3K14 ubiquitylation promotes H3K9 methylation for heterochromatin assembly."
Abo1 is required for the H3K9me2 to H3K9me3 transition in heterochromatin.
The histone H3K9M mutation synergizes with H3K14 ubiquitylation to selectively sequester histone H3K9 methyltransferase Clr4 at heterochromatin.
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H3K9M and H3K14ub together selectively sequester Clr4 at pericentric heterochromatin, demonstrating Clr4 reading of ubiquitin-modified histone.
"The histone H3K9M mutation synergizes with H3K14 ubiquitylation to selectively sequester histone H3K9 methyltransferase Clr4 at heterochromatin."
SUV39 SET domains mediate crosstalk of heterochromatic histone marks.
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The Clr4 catalytic domain contains a ubiquitin-binding region that binds H3K14ub and stimulates the enzyme >250-fold; disrupting it abolishes heterochromatin silencing like clr4 deletion. Clr4 is the sole H3K9me2/3 methyltransferase of S. pombe.
"the H3K14ub substrate binds specifically and tightly to the catalytic domain of Clr4, and thereby stimulates the enzyme by over 250-fold. Mutations that disrupt this mechanism lead to a loss of H3K9me2/3 and abolish heterochromatin silencing similar to clr4 deletion."
Mechanistic insights into the stimulation of the histone H3K9 methyltransferase Clr4 by proximal H3K14 ubiquitination.
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Crystal structures of the Clr4 KMT (pre-SET/SET/post-SET) catalytic domain bound to H3 peptide and SAM cofactor reveal the SAM-dependent H3K9 methyltransferase active site and the multivalent ubiquitin interface by which proximal H3K14 ubiquitination stimulates H3K9me2/3 deposition.
"The SAM cofactor is located on the larger side of the ovoid structure, embedded in the SAM pocket of the SET domain, with the post-SET subdomain covering above as a lid."
Intrinsically disordered region of Clr4/Suv39 regulates its enzymatic activity and ensures heterochromatin spreading.
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The intrinsically disordered region of Clr4 regulates its H3K9 methyltransferase activity and is required for heterochromatin spreading.
"Intrinsically disordered region of Clr4/Suv39 regulates its enzymatic activity and ensures heterochromatin spreading."
Three additional linkage groups that repress transcription and meiotic recombination in the mating-type region of Schizosaccharomyces pombe.
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clr4 (with clr2, clr3) is a trans-acting locus required for transcriptional and recombinational silencing at the mating-type region.
"the transcription and recombination blocks require three newly defined trans-acting loci, clr2, clr3 and clr4, in addition to the previously identified clr1, rik1 and swi6 loci."