Transcription coactivator p300 binds PCNA and may have a role in DNA repair synthesis

Hasan, Sameez; Hassa, Paul O.; Imhof, Ralph; Hottiger, Michael O.

doi:10.1038/35066610

Cited by 154 publications

(147 citation statements)

References 29 publications

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“…The latter occurs however in a NER independent manner [79]. Moreover, the HAT p300 activates transcription through chromatin remodelling and interactions with the basal transcription machinery including RNAPII and interacts with DNA repair proteins, such as DDB1 and PCNA [82,83]. Evidence has been gained for a role of the nucleosome binding protein HMGN1 in mammalian TC-NER.…”

Section: Recruitment Of Chromatin Remodellers In Tc-nermentioning

confidence: 99%

Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects

2008

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The encounter of elongating RNA polymerase II (RNAPIIo) with DNA lesions has severe consequences for the cell as this event provides a strong signal for P53-dependent apoptosis and cell cycle arrest. To counteract prolonged blockage of transcription, the cell removes the RNAPIIo-blocking DNA lesions by transcription-coupled repair (TC-NER), a specialized subpathway of nucleotide excision repair (NER). Exposure of mice to UVB light or chemicals has elucidated that TC-NER is a critical survival pathway protecting against acute toxic and long-term effects (cancer) of genotoxic exposure. Deficiency in TC-NER is associated with mutations in the CSA and CSB genes giving rise to the rare human disorder Cockayne syndrome (CS). Recent data suggest that CSA and CSB play differential roles in mammalian TC-NER: CSB as a repair coupling factor to attract NER proteins, chromatin remodellers and the CSA-E3-ubiquitin ligase complex to the stalled RNAPIIo. CSA is dispensable for attraction of NER proteins, yet in cooperation with CSB is required to recruit XAB2, the nucleosomal binding protein HMGN1 and TFIIS. The emerging picture of TC-NER is complex: repair of transcription-blocking lesions occurs without displacement of the DNA damage-stalled RNAPIIo, and requires at least two essential assembly factors (CSA and CSB), the core NER factors (except for XPC-RAD23B), and TC-NER specific factors. These and yet unidentified proteins will accomplish not only efficient repair of transcription-blocking lesions, but are also likely to contribute to DNA damage signalling events.

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Section: Recruitment Of Chromatin Remodellers In Tc-nermentioning

confidence: 99%

Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects

2008

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“…The region of p300 that mediates the interaction between PCNA and p300 has been mapped to the C-terminal region of p300 outside its HAT domain (35). But the corresponding region on PCNA has not been determined.…”

Section: Pcna Selectively Inhibits the Hat Activity Of P300 In Vitro-mentioning

confidence: 99%

“…2A). 35 S-Labeled PCNA was incubated with approximately equal amounts of beads-bound recombinant FLAG-tagged p300 or PCAF. PCNA was also incubated with histones and immunoprecipitated with pan-histone antibodies to determine whether PCNA may block p300 HAT activity by binding to histones.…”

Section: Pcna Selectively Inhibits the Hat Activity Of P300 In Vitro-mentioning

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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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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“…GST fusion proteins and in vitro binding assay pGST/B-Myb-D3, pGST/B-Myb-DFsp, GST/p300(1-672), GST/p300(672-1193), GST/p300(1710-1891) and GST/ p300(1883-1927) have been described elsewhere (Horstmann et al, 2000a;Hasan et al, 2001;Schwartz et al, 2003). GST fusion protein expression was induced in logarithmically growing cultures of transformed bacteria (E. coli BL21-lys) by adding isopropyl-b-D-thiogalactopyranoside (IPTG) to a final concentration of 0.5 mM.…”

Section: Reporter Genes Transfections Luciferase and B-galactosidasmentioning

confidence: 99%

The cooperation of B-Myb with the coactivator p300 is orchestrated by cyclins A and D1

et al. 2004

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B-Myb is a highly conserved member of the Myb family of transcription factors whose activity is regulated during the cell cycle. Previous work has shown that the activity of BMyb is stimulated by cyclin A/Cdk2-dependent phosphorylation whereas interaction of B-Myb with cyclin D1 inhibits its activity. Here, we have investigated the role of p300 as a coactivator for B-Myb. We show that B-Mybdependent transactivation is stimulated by p300 as a result of interaction between B-Myb and p300. We have mapped the sequences responsible for the interaction of B-Myb and p300 to the E1A-binding region of p300 and the transactivation domain of B-Myb, respectively. Furthermore, our data suggest that phosphorylation of B-Myb stimulates its acetylation by p300 and that the acetylation of B-Myb is necessary for the full stimulation of its transactivation potential by p300. We have also studied the effect of cyclin D1 on the cooperation of B-Myb and p300. Based on our results we propose that cyclin D1 inhibits the activity of B-Myb by interfering with the interaction of B-Myb and p300. The data reported here provide novel insight into the mechanisms by which the activity of B-Myb is regulated during the cell cycle. Taken together they suggest that the coactivator p300 plays an important role in this regulation and that the cooperation of B-Myb and p300 is orchestrated by cyclins A and D1.

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Transcription coactivator p300 binds PCNA and may have a role in DNA repair synthesis

Cited by 154 publications

References 29 publications

Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects

Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects

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

The cooperation of B-Myb with the coactivator p300 is orchestrated by cyclins A and D1

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