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Phosphorylation of an HP1-like protein regulates RNA-bridged heterochromatin body assembly for DNA elimination

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Tetrahymena thermophila

PROVIDER: GSE70083 | GEO | 2015/12/10

SECONDARY ACCESSION(S): PRJNA287577

REPOSITORIES: GEO

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Phosphorylation of an HP1-like protein regulates RNA-bridged heterochromatin body assembly for DNA elimination

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-12-10 | E-GEOD-70083 | biostudies-arrayexpress

Phosphorylation of an HP1-like Protein Regulates Heterochromatin Body Assembly for DNA Elimination.

Project description:Heterochromatic loci are often assembled into higher-order heterochromatin bodies in diverse eukaryotes. However, the formation and biological roles of heterochromatin bodies are poorly understood. In the ciliated protozoan Tetrahymena, de novo heterochromatin body formation is accompanied by programmed DNA elimination. Here, we show that the heterochromatin body component Jub1p promotes heterochromatin body formation and dephosphorylation of the Heterochromatin Protein 1-like protein Pdd1p. Through the mutagenesis of the phosphorylated residues of Pdd1p, we demonstrate that Pdd1p dephosphorylation promotes the electrostatic interaction between Pdd1p and RNA in vitro and heterochromatin body formation in vivo. We therefore propose that heterochromatin body is assembled by the Pdd1p-RNA interaction. Pdd1p dephosphorylation and Jub1p are required for heterochromatin body formation and DNA elimination but not for local heterochromatin assembly, indicating that heterochromatin body plays an essential role in DNA elimination.

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Jub4p-mediated phosphorylation of Pdd1p is a prerequisite for heterochromatin body assembly and DNA elimination

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-07-15 | E-GEOD-83252 | biostudies-arrayexpress

Phosphorylation of an HP1-like protein is a prerequisite for heterochromatin body formation in Tetrahymena DNA elimination.

Project description:Multiple heterochromatic loci are often clustered into a higher order nuclear architecture called a heterochromatin body in diverse eukaryotes. Although phosphorylation of Heterochromatin Protein 1 (HP1) family proteins regulates heterochromatin dynamics, its role in heterochromatin bodies remains unknown. We previously reported that dephosphorylation of the HP1-like protein Pdd1p is required for the formation of heterochromatin bodies during the process of programmed DNA elimination in the ciliated protozoan Tetrahymena Here, we show that the heterochromatin body component Jub4p is required for Pdd1p phosphorylation, heterochromatin body formation, and DNA elimination. Moreover, our analyses of unphosphorylatable Pdd1p mutants demonstrate that Pdd1p phosphorylation is required for heterochromatin body formation and DNA elimination, whereas it is dispensable for local heterochromatin assembly. Therefore, both phosphorylation and the following dephosphorylation of Pdd1p are necessary to facilitate the formation of heterochromatin bodies. We suggest that Jub4p-mediated phosphorylation of Pdd1p creates a chromatin environment that is a prerequisite for subsequent heterochromatin body assembly and DNA elimination.

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Jub4p-mediated phosphorylation of Pdd1p is a prerequisite for heterochromatin body assembly and DNA elimination

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-07-15 | GSE83252 | GEO

Kruppel-associated Box (KRAB)-associated co-repressor (KAP-1) Ser-473 phosphorylation regulates heterochromatin protein 1? (HP1-?) mobilization and DNA repair in heterochromatin.

Project description:The DNA damage response encompasses a complex series of signaling pathways that function to regulate and facilitate the repair of damaged DNA. Recent studies have shown that the repair of transcriptionally inactive chromatin, named heterochromatin, is dependent upon the phosphorylation of the co-repressor, Krüppel-associated box (KRAB) domain-associated protein (KAP-1), by the ataxia telangiectasia-mutated (ATM) kinase. Co-repressors, such as KAP-1, function to regulate the rigid structure of heterochromatin by recruiting histone-modifying enzymes, such HDAC1/2, SETDB1, and nucleosome-remodeling complexes such as CHD3. Here, we have characterized a phosphorylation site in the HP1-binding domain of KAP-1, Ser-473, which is phosphorylated by the cell cycle checkpoint kinase Chk2. Expression of a nonphosphorylatable S473A mutant conferred cellular sensitivity to DNA-damaging agents and led to defective repair of DNA double-strand breaks in heterochromatin. In addition, cells expressing S473A also displayed defective mobilization of the HP1-? chromodomain protein. The DNA repair defect observed in cells expressing S473A was alleviated by depletion of HP1-?, suggesting that phosphorylation of KAP-1 on Ser-473 promotes the mobilization of HP1-? from heterochromatin and subsequent DNA repair. These results suggest a novel mechanism of KAP-1-mediated chromatin restructuring via Chk2-regulated HP1-? exchange from heterochromatin, promoting DNA repair.

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BRD4 facilitates DNA damage response and represses CBX5/Heterochromatin protein 1 (HP1).

Project description:Ovarian cancer (OC) is a heterogeneous disease characterized by defective DNA repair. Very few targets are universally expressed in the high grade serous (HGS) subtype. We previously identified that CHK1 was overexpressed in most of HGSOC. Here, we sought to understand the DNA damage response (DDR) to CHK1 inhibition and increase the anti-tumor activity of this pathway. We found BRD4 suppression either by siRNA or BRD4 inhibitor JQ1 enhanced the cytotoxicity of CHK1 inhibition. Interestingly, BRD4 was amplified and/or upregulated in a subset of HGSOC with statistical correlation to overall survival. BRD4 inhibition increased CBX5 (HP1α) level. CHK1 inhibitor induced DDR marker, γ-H2AX, but BRD4 suppression did not. Furthermore, nuclear localization of CBX5 and γ-H2AX was mutually exclusive in BRD4-and CHK1-inhibited cells, suggesting BRD4 facilitates DDR by repressing CBX5. Our results provide a strong rationale for clinical investigation of CHK1 and BRD4 co-inhibition, especially for HGSOC patients with BRD4 overexpression.

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DNA elimination analysis of Tetrahymena cells defective in heterochromatin body formation

Project description:In the ciliated protozoan Tetrahymena, de novo heterochromatin body formation is accompanied by programmed DNA elimination. Here, we show that the novel heterochromatin body component Jub1p promotes heterochromatin body formation and dephosphorylation of the Heterochromatin Protein 1 (HP1)-like protein Pdd1p. Through the identification and mutagenesis of the phosphorylated residues of Pdd1p, we demonstrate that Pdd1p dephosphorylation promotes the electrostatic interaction between Pdd1p and RNA in vitro and heterochromatin body formation in vivo. We therefore suggest that heterochromatin bodies are assembled by the Pdd1p-RNA interaction. Jub1p and Pdd1p dephosphorylation are required for heterochromatin body formation and DNA elimination but not for local heterochromatin assembly, indicating that heterochromatin body of itself plays an essential role in DNA elimination. Micronuclei (MICs) and new macronuclei (MACs) of exconjugants were isolated from different mutants at 36 hpm, and the genomic DNA was analyzed by high-throughput sequencing.

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Linking Heterochromatin Protein 1 (HP1) to cancer progression.

Project description:All cells of a given organism contain nearly identical genetic information, yet tissues display unique gene expression profiles. This specificity is in part due to transcriptional control by epigenetic mechanisms that involve post-translational modifications of histones. These modifications affect the folding of the chromatin fiber and serve as binding sites for non-histone chromosomal proteins. Here we discuss functions of the Heterochromatin Protein 1 (HP1) family of proteins that recognize H3K9me, an epigenetic mark generated by the histone methyltransferases SU(VAR)3-9 and orthologues. Loss of HP1 proteins causes chromosome segregation defects and lethality in some organisms; a reduction in levels of HP1 family members is associated with cancer progression in humans. These consequences are likely due to the role of HP1 in centromere stability, telomere capping and the regulation of euchromatic and heterochromatic gene expression.

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Jub4p-mediated phosphorylation of Pdd1p is a prerequisite for heterochromatin body assembly and DNA elimination

Project description:Jub4p-mediated phosphorylation of Pdd1p is a prerequisite for heterochromatin body assembly and DNA elimination

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