Mutagen sensitivity and suppression of position-effect variegation result from mutations in mus209, the Drosophila gene encoding PCNA.

Henderson, Daryl S.; Banga, Satnam S.; Grigliatti, Thomas A.; Boyd, James B.

doi:10.1002/j.1460-2075.1994.tb06399.x

Cited by 131 publications

(59 citation statements)

References 70 publications

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“…In Drosophila, the PCNA mutant mus209B1 shows suppression of position effect variegation in addition to its hypersensitivity to DNA damage. These results provided strong genetic proof for the role of Drosophila PCNA in transcriptional repression and heterochromatin maintenance (33). Again, the mechanism by which Drosophila PCNA may mediate repression was not established.…”

Section: Discussionmentioning

confidence: 94%

“…In Saccharomyces cerevisiae, PCNA is involved in gene silencing through CAF-1-dependent and -independent mechanisms (32). In Drosophila, mutation of PCNA suppresses position effect variegation (33), indicating its role in transcriptional repression and heterochromatin function. In mammals, PCNA was shown to interact with histone deacetylase 1(HDAC1), implying a role for histone hypo-acetylation in DNA replication (34).…”

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confidence: 99%

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The Human Proliferating Cell Nuclear Antigen Regulates Transcriptional Coactivator p300 Activity and Promotes Transcriptional Repression

Hong

Chakravarti

2003

Journal of Biological Chemistry

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Chromatin structure plays an important role in DNA replication, repair, and transcription. p300 is a transcriptional coactivator with protein acetyltransferase activity, and proliferating cell nuclear antigen (PCNA) plays important roles in DNA replication and repair. It has been shown recently that p300 is necessary for DNA synthesis and repair. However, it is not known whether human PCNA, in a reciprocal manner, can regulate the enzymatic activity and transcriptional regulatory properties of p300. Here we show that human PCNA associates with p300 and potently inhibits the acetyltransferase activity and transcriptional activation properties of p300. Surprisingly, PCNA fails to inhibit p300/CBPassociated factor (PCAF) acetyltransferase function as well as PCAF-dependent transcription. Additionally, PCNA potently represses transcription when targeted to chromatin in vivo. Consistent with these observations, using chromatin immunoprecipitation assays, we demonstrate that PCNA recruitment to promoters causes hypoacetylation of chromatin. Together, our results demonstrate for the first time a novel role for human PCNA in transcriptional repression and in modulating chromatin modification. The reciprocal modulation of p300 and PCNA activities by each other provides an example of integrative regulatory cross-talk among chromatin-based processes such as DNA transcription, repair, and synthesis.

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Section: Discussionmentioning

confidence: 94%

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confidence: 99%

The Human Proliferating Cell Nuclear Antigen Regulates Transcriptional Coactivator p300 Activity and Promotes Transcriptional Repression

Hong

Chakravarti

2003

Journal of Biological Chemistry

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“…A recent study in Saccharomyces cerevisiae has shown that several mutations in PCNA decrease silencing at telomeres and at the mating-type HMR locus (7). Furthermore, mutations in the Drosophila PCNA gene mus209 suppress repression in the vicinity of heterochromatin (8). The disruption of epigenetic silencing has been attributed to the inability of some of these mutants to associate with CAF-1.…”

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confidence: 99%

Proliferating Cell Nuclear Antigen Associates with Histone Deacetylase Activity, Integrating DNA Replication and Chromatin Modification

Milutinovic¹,

Zhuang

Szyf

2002

Journal of Biological Chemistry

102

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Faithful inheritance of the chromatin structure is essential for maintaining the gene expression integrity of a cell. Histone modification by acetylation and deacetylation is a critical control of chromatin structure. In this study, we test the hypothesis that histone deacetylase 1 (HDAC1) is physically associated with a basic component of the DNA replication machinery as a mechanism of coordinating histone deacetylation and DNA synthesis. Proliferating cell nuclear antigen (PCNA) is a sliding clamp that serves as a loading platform for many proteins involved in DNA replication and DNA repair. We show that PCNA interacts with HDAC1 in human cells and in vitro and that a considerable fraction of PCNA and HDAC1 colocalize in the cell nucleus. PCNA associates with histone deacetylase activity that is completely abolished in the presence of the HDAC inhibitor trichostatin A. Trichostatin A treatment arrests cells at the G 2 -M phase of the cell cycle, which is consistent with the hypothesis that the proper formation of the chromatin after DNA replication may be important in signaling the progression through the cell cycle. Our results strengthen the role of PCNA as a factor coordinating DNA replication and epigenetic inheritance.Epigenetic markings play an essential role in regulating the gene expression program of vertebrate cells. One of the fundamental challenges of cell division is therefore coordinating the processes of genetic and epigenetic inheritance. The cell must possess multiple mechanisms to coordinate these processes (1). For example, DNA methylation is coordinated with DNA replication (2) by physical association of maintenance DNA methyltransferase 1 with the DNA replication fork protein PCNA 1 (3). Inhibition of DNA methyltransferase 1 leads to inhibition of initiation of DNA replication (4).Similar to DNA methylation, DNA replication-coupled chromatin assembly is essential for the inheritance of the epigenetic code. The specific targeting of nucleosome assembly to the newly synthesized DNA is achieved by direct interaction of histone chaperone CAF-1 with PCNA (5). PCNA is a homotrimeric protein that forms a sliding clamp around DNA and functions as a DNA polymerase processivity factor during replication and nucleotide excision repair. Through its multiple protein-protein interactions, PCNA coordinates events in replication, epigenetic inheritance, repair, and cell cycle control (6). A recent study in Saccharomyces cerevisiae has shown that several mutations in PCNA decrease silencing at telomeres and at the mating-type HMR locus (7). Furthermore, mutations in the Drosophila PCNA gene mus209 suppress repression in the vicinity of heterochromatin (8). The disruption of epigenetic silencing has been attributed to the inability of some of these mutants to associate with CAF-1. However, synergism of several PCNA mutants with CAF-1 mutants suggested that PCNA may participate in silencing through another factor.During nucleosome assembly, histones H3 and H4 undergo transient acetylation before their deposi...

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“…Mutations in DNA replication factors lead to defects in position-effect variegation in flies (36)(37)(38) and silencing defects at telomeres and silent mating loci in yeast (39)(40)(41). Likewise, perturbations of cellular acyl pools in yeast by genetic inactivation orthologs of Acaca (42) and Acss1 (43) cause global alterations in histone acetylation and genomewide expression.…”

Section: Discussionmentioning

confidence: 99%

Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP/TGF-β superfamily as a regulator of XIST expression

Sripathy

Leko

Adrianse

et al. 2017

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

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Rett syndrome (RS) is a debilitating neurological disorder affecting mostly girls with heterozygous mutations in the gene encoding the methyl-CpG-binding protein MeCP2 on the X chromosome. Because restoration of MeCP2 expression in a mouse model reverses neurologic deficits in adult animals, reactivation of the wild-type copy of MeCP2 on the inactive X chromosome (Xi) presents a therapeutic opportunity in RS. To identify genes involved in MeCP2 silencing, we screened a library of 60,000 shRNAs using a cell line with a MeCP2 reporter on the Xi and found 30 genes clustered in seven functional groups. More than half encoded proteins with known enzymatic activity, and six were members of the bone morphogenetic protein (BMP)/TGF-β pathway. shRNAs directed against each of these six genes down-regulated X-inactive specific transcript (XIST), a key player in X-chromosome inactivation that encodes an RNA that coats the silent X chromosome, and modulation of regulators of this pathway both in cell culture and in mice demonstrated robust regulation of XIST. Moreover, we show that Rnf12, an X-encoded ubiquitin ligase important for initiation of X-chromosome inactivation and XIST transcription in ES cells, also plays a role in maintenance of the inactive state through regulation of BMP/TGF-β signaling. Our results identify pharmacologically suitable targets for reactivation of MeCP2 on the Xi and a genetic circuitry that maintains XIST expression and X-chromosome inactivation in differentiated cells.XIST | X inactivation | MeCP2 | Rett syndrome | BMP/TGF-β

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Mutagen sensitivity and suppression of position-effect variegation result from mutations in mus209, the Drosophila gene encoding PCNA.

Cited by 131 publications

References 70 publications

The Human Proliferating Cell Nuclear Antigen Regulates Transcriptional Coactivator p300 Activity and Promotes Transcriptional Repression

The Human Proliferating Cell Nuclear Antigen Regulates Transcriptional Coactivator p300 Activity and Promotes Transcriptional Repression

Proliferating Cell Nuclear Antigen Associates with Histone Deacetylase Activity, Integrating DNA Replication and Chromatin Modification

Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP/TGF-β superfamily as a regulator of XIST expression

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