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The 19S proteasome subunit Rpt3 regulates distribution of CENP-A by associating with centromeric chromatin

ABSTRACT: CENP-A, a variant of histone H3, is incorporated into centromeric chromatin and plays a role during kinetochore establishment. In fission yeast, the localization of CENP-A is limited to a region spanning 10 to 20 kb of the core domain of the centromere. Here, we report a mutant (rpt3-1) in which this region is expanded to 40 to 70 kb. Likely due to abnormal distribution of CENP-A, this mutant exhibits chromosome instability and enhanced gene silencing. Interestingly, the rpt3+ gene encodes a subunit of the 19S proteasome, which localizes to the nuclear membrane. While Rpt3 associates with centromeric chromatin, the mutant protein has lost this localization. A loss of the cut8+ gene encoding an anchor of the proteasome to the nuclear membrane causes similar phenotypes as observed in the rpt3-1 mutant. Thus, we propose that the proteasome (or its subcomplex) associates with centromeric chromatin and regulates distribution of CENP-A.

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE44594 | GEO | 2014/04/07

SECONDARY ACCESSION(S): PRJNA190604

REPOSITORIES: GEO

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The 19S proteasome subunit Rpt3 regulates distribution of CENP-A by associating with centromeric chromatin

Project description:CENP-A, a variant of histone H3, is incorporated into centromeric chromatin and plays a role during kinetochore establishment. In fission yeast, the localization of CENP-A is limited to a region spanning 10 to 20 kb of the core domain of the centromere. Here, we report a mutant (rpt3-1) in which this region is expanded to 40 to 70 kb. Likely due to abnormal distribution of CENP-A, this mutant exhibits chromosome instability and enhanced gene silencing. Interestingly, the rpt3+ gene encodes a subunit of the 19S proteasome, which localizes to the nuclear membrane. While Rpt3 associates with centromeric chromatin, the mutant protein has lost this localization. A loss of the cut8+ gene encoding an anchor of the proteasome to the nuclear membrane causes similar phenotypes as observed in the rpt3-1 mutant. Thus, we propose that the proteasome (or its subcomplex) associates with centromeric chromatin and regulates distribution of CENP-A. Chromosomal distributions of differentially expressed centromere protein A in wild-type and a proteasome mutant.

2014-04-07 | E-GEOD-44594 | biostudies-arrayexpress

Schizosaccharomyces pombe

Project description:The 19S proteasome subunit Rpt3 regulates distribution of CENP-A by associating with centromeric chromatin

| PRJNA190604 | ENA

The N-terminal Tail of CENP-A Confers Epigenetic Stability to Centromeres via the CENP-T Branch of the CCAN in Fission Yeast

Project description:We employ the well-studied fission yeast centromere to investigate the function of the CENP-A (Cnp1) N-tail. We show that alteration of the N-tail did not affect Cnp1 loading at centromeres, outer kinetochore formation, or spindle checkpoint signaling, but nevertheless elevated chromosome loss. N-Tail mutants exhibited synthetic lethality with an altered centromeric DNA sequence, with rare survivors harboring chromosomal fusions in which the altered centromere was epigenetically inactivated. Elevated centromere inactivation was also observed for N-tail mutants with unaltered centromeric DNA sequences. N-tail mutants specifically reduced localization of the CCAN proteins Cnp20/CENP-T and Mis6/CENP-I, but not Cnp3/CENP-C. Overexpression of Cnp20/CENP-T suppressed defects in an N-tail mutant, suggesting a causal link between reduced CENP-T recruitment and the observed centromere inactivation phenotype. Thus, the Cnp1 N-tail promotes epigenetic stability of centromeres via recruitment of the CENP-T branch of the CCAN. Genome-wide localization of GFP-tagged N-tail Cnp1 variant tailswap versus wt control in cnp1 deletion background

2015-04-16 | E-GEOD-63350 | biostudies-arrayexpress

Re-localization of CENP-A at centromeres upon depletion and re-expression

Project description:In a human cell line centromeric protein CENP-A was removed and then re-expressed. Possible subsequent changes in CENP-A localization were investigated with CUT&RUN-seq.

2020-09-22 | GSE148187 | GEO

Ccp1 homodimer mediates chromatin integrity by antagonizing CENP-A loading

Project description:CENP-A is a centromere-specific histone 3 variant essential for centromere specification. CENP-A partially replaces canonical histone H3 at the centromeres. How the particular CENP-A/H3 ratio at centromeres is precisely maintained is unknown. It also remains unclear how CENP-A is excluded from non-centromeric chromatin. Here we identify Ccp1, an uncharacterized NAP family protein in fission yeast that antagonizes CENP-A loading at both centromeric and non-centromeric regions. Like the CENP-A loading factor HJURP, Ccp1 interacts with CENP-A, and is recruited to centromeres at the end of mitosis in a Mis16-dependent manner. These data indicate that factors with opposing CENP-A loading activities are recruited to centromeres. Furthermore, Ccp1 also cooperates with H2A.Z to evict CENP-A assembled in euchromatin. Structural analyses indicate that Ccp1 forms a homodimer that is required for its anti-CENP-A loading activity. Our study establishes mechanisms for maintenance of CENP-A homeostasis at centromeres and the prevention of ectopic assembly of centromeres. Examination of cnp1 distribution in one wild type (wt) and two ccp1 mutants.

2016-08-04 | E-GEOD-85166 | biostudies-arrayexpress

Deposition of centromeric histone H3 variant CENP-A/Cse4 into chromatin is facilitated by its C-terminal sumoylation

Project description:Centromeric localization of CENP-A (Cse4 in S. cerevisiae, CID in flies, CENP-A in humans) is essential for faithful chromosome segregation. Overexpression of CENP-A leads to its mislocalization and contributes to aneuploidy in yeast, flies, humans and is proposed to promote tumorigenesis in human cancers. Hence, defining molecular mechanisms that promote or prevent mislocalization of CENP-A is an area of active investigation. In budding yeast, evolutionarily conserved histone chaperones Scm3 and chromatin assembly factor-1 (CAF-1) promote localization of Cse4 to centromeric and non-centromeric regions, respectively. Ubiquitin ligases such as Psh1 and Slx5 and histone chaperones (HIR complex) regulate proteolysis of overexpressed Cse4 and prevent its mislocalization to non-centromeric regions. In this study, we have identified sumoylation sites lysine (K) 215/216 in the C-terminus of Cse4 and shown that sumoylation of Cse4 K215/216 facilitates its genome-wide deposition into chromatin when overexpressed. Our results showed reduced levels of sumoylation of mutant Cse4 K215/216R/A (K changed to arginine (R) or alanine (A)) and reduced interaction of mutant Cse4 K215/215R/A with Scm3 and CAF-1 when compared to wild type Cse4. Consistent with these results, levels of Cse4 K215/216R/A in the chromatin fraction at centromeric and non-centromeric regions were reduced. Furthermore, in contrast to GAL-CSE4 which exhibits Synthetic Dosage Lethality (SDL) in psh1Æ, slx5Æ, and hir2Æ strains, GAL-cse4 K215/216R does not exhibit SDL in these strains. Taken together, our results identify and define a role for C-terminal sumoylation of Cse4 for its incorporation into chromatin.

2020-02-21 | GSE145602 | GEO

The N-terminal Tail of CENP-A Confers Epigenetic Stability to Centromeres via the CENP-T Branch of the CCAN in Fission Yeast

2015-04-16 | GSE63350 | GEO

DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of H3-H4 supply chains

Project description:The centromeric histone H3 variant CENP-A is overexpressed in many cancers. Mislocalization of CENP-A to non-centromeric regions contributes to chromosomal instability (CIN), a hallmark of cancer. Despite these observations, pathways that promote and prevent CENP-A mislocalization remain poorly defined. Here, we performed a genome-wide RNAi screen to identify regulators of CENP-A localization. We identified DNAJC9, a J-domain protein as a lead candidate from the screen and showed that cells depleted for DNAJC9 exhibit mislocalization of CENP-A, enrichment of CENP-A in chromatin, and CIN phenotypes. Global interactome analysis showed an enhanced interaction of CENP-A with the replication-associated H3-H4 chaperone MCM2 in DNAJC9-depleted cells and co-depletion of MCM2 and DNAJC9 suppressed CENP-A mislocalization. Furthermore, we showed that cells ablated for the ability of DNAJC9 to promote the proper folding of H3–H4, exhibit CENP-A mislocalization. CUT&RUN Sequencing analysis of genome-wide CENP-A occupancy in DNAJC9-depleted cells identified 16,603 sites of non-centromeric localization, that broadly overlapped with open chromatin regions. Our comprehensive analysis has identified factors that prevent mislocalization of CENP-A and has defined DNAJC9 as an important safeguard that prevents CENP-A mislocalization and CIN.

2024-03-26 | GSE253387 | GEO

ChIP-chip from four orangutan cells with CENP-A

Project description:In the present study we analyzed centromeric localization on chromosome 12 in different orangutan and results showed that each individual exhibits a different arrangement of CENP-A binding domains.

2017-01-01 | GSE81003 | GEO

ChIP-chip from five horse cells with CENP-A

Project description:In the present study we analyzed centromeric localization on chromosome 11 in different horses and results showed that each individual exhibits a different arrangement of CENP-A binding domains.

2015-01-01 | GSE57986 | GEO

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