Regulation of Human Flap Endonuclease-1 Activity by Acetylation through the Transcriptional Coactivator p300

Hasan, Sameez; Stucki, Manuel; Hassa, Paul O.; Imhof, Ralph; Gehrig, Peter; Hunziker, Peter; Hübscher, Ulrich; Hottiger, Michael O.

doi:10.1016/s1097-2765(01)00272-6

Cited by 151 publications

(168 citation statements)

References 39 publications

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“…p300 was previously indicated as a potential acetyltransferase able to modify BER pathway proteins, including Pol b, OGG1, RPA, PCNA and FEN1. 14,17,18,38,43 As shown in Fig. 7, no differences were observed in relative EGFP levels for the 8-oxoG containing plasmid (GO), as well as for GO:MC6, for both HCT116 cell lines.…”

Section: Efficiency Of Ber Is Not Significantly Altered In Cells Expomentioning

confidence: 76%

“…15 A positive effect of acetylation on strand displacement synthesis was also observed in reconstituted systems simulating Okazaki fragments synthesis. [16][17][18] The effect of acetylation on proteins involved in DNA mismatch repair (MMR) was investigated in less detail. Here, acetylation of K residues at the C termini of MSH2, an especial component of the complex recognizing mismatches in DNA, had a positive effect on repair.…”

Section: Introductionmentioning

confidence: 99%

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Acetylation regulates DNA repair mechanisms in human cells

2016

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The p300-mediated acetylation of enzymes involved in DNA repair and replication has been previously shown to stimulate or inhibit their activities in reconstituted systems. To explore the role of acetylation on DNA repair in cells we constructed plasmid substrates carrying inactivating damages in the EGFP reporter gene, which should be repaired in cells through DNA mismatch repair (MMR) or base excision repair (BER) mechanisms. We analyzed efficiency of repair within these plasmid substrates in cells exposed to deacetylase and acetyltransferase inhibitors, and also in cells deficient in p300 acetyltransferase. Our results indicate that protein acetylation improves DNA mismatch repair in MMR-proficient HeLa cells and also in MMR-deficient HCT116 cells. Moreover, results suggest that stimulated repair of mismatches in MMR-deficient HCT116 cells is done though a strand-displacement synthesis mechanism described previously for Okazaki fragments maturation and also for the EXOI-independent pathway of MMR. Loss of p300 reduced repair of mismatches in MMR-deficient cells, but did not have evident effects on BER mechanisms, including the long patch BER pathway. Hypoacetylation of the cells in the presence of acetyltransferase inhibitor, garcinol generally reduced efficiency of BER of 8-oxoG damage, indicating that some steps in the pathway are stimulated by acetylation.

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Section: Efficiency Of Ber Is Not Significantly Altered In Cells Expomentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Acetylation regulates DNA repair mechanisms in human cells

2016

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“…Interestingly, general transcription factor 2B (GTF2B, also known as TFIIB) has been reported to behave as an auto-acetyltransferase, and acetylation regulates its activity 32 . Acetylation also impairs the catalytic and DNA-binding activities of enzymes involved in DNA metabolism and repair 33,34 .…”

Section: At a Glancementioning

confidence: 99%

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

2006

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| Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.Histone deacetylases (HDACs) have been intensively scrutinized over the past few years for two main reasons. First, they have been linked mechanistically to the pathogenesis of cancer, as well as several other diseases. Second, small-molecule HDAC inhibitors (HDACi) exist that have the capacity to interfere with HDAC activity and can therefore achieve significant biological effects in preclinical models of cancer. These findings justified the introduction of HDACi into clinical trials. These initial clinical trials have just ended and show encouraging results. At this stage it is crucial to evaluate whether our current knowledge on the mechanisms of tumorigenesis that are linked to HDACs, and on the mechanisms of tumour sensitivity to HDACi, is firm enough to improve the design of further clinical trials. Recent structural and chemical data have emerged that will help in the design of novel HDACi with more desirable properties than the existing ones. However, key areas of investigation that might help to further illuminate the design of successful HDACi-based cancer therapy remain poorly explored. Novel findings indicate that our understanding of how HDACi work will probably change significantly, establishing a new paradigm in the field of intelligent drug design with broad implications for the design of targeted therapies in cancer and possibly other diseases.HDACs: enzymes looking for substrate(s) Four HDAC classes have been identified (FIG. 1a). One of them (class 3 or the so-called sirtuins, from the yeast protein Sir2) constitutes a structurally unrelated, NADdependent subfamily, and will not be considered here; neither will the class 3-specific HDACi, which are less characterized than those for the other classes 1 .An extensive phylogenetic analysis of HDACs has been performed 2,3 . HDACs are members of an ancient enzyme family found in animals, plants, fungi and bacteria. It is thought that HDACs evolved in the absence of histone proteins. Indeed, eukaryotic HDACs can deacetylate non-histone as well as histone substrates, and some HDACs reside in the cytoplasm (where histones are synthesized and acetylated for proper assembly, without the intervention of HDACs) and in mitochondria (where histones are absent).Are HDACs, then, truly HDACs 4 ? We postulate that key HDAC substrates might not be histones, but instead belong to the growing list of acetylated non-histone proteins (FIG. 1b and Supplementary information S1 ...

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“…Fen1 functionally and physically interacts with pol ß to promote strand displacement and flap hydrolysis [11,120]. The functionality of Fen1 is further modified by phosphorylation [121] and acetylation [122,123], each modification providing a different level of regulation. Whereas phosphorylation prevents Fen1-mediated stimulation of PCNA, acetylation by p300 appears to reduce the ability of Fen1 to bind to DNA and to function as a nuclease, with no effect on its PCNA interaction (Table III).…”

Section: Post-translational Modifications Of Ber Gap Tailoring Proteinsmentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

385

374

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Base excision repair (BER) proteins act upon a significantly broad spectrum of DNA lesions that result from endogenous and exogenous sources. Multiple sub-pathways of BER (short-path or longpatch) and newly designated DNA repair pathways (e.g., SSBR and NIR) that utilize BER proteins complicate any comprehensive understanding of BER and its role in genome maintenance, chemotherapeutic response, neurodegeneration, cancer or aging. Herein, we propose a unified model of BER, comprised of three functional processes: Lesion Recognition/Strand Scission, Gap Tailoring and DNA Synthesis/Ligation, each represented by one or more multiprotein complexes and coordinated via the XRCC1/DNA Ligase III and PARP1 scaffold proteins. BER therefore may be represented by a series of repair complexes that assemble at the site of the DNA lesion and mediates repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Complex formation is influenced by post-translational protein modifications that arise from the cellular state or the DNA damage response, providing an increase in specificity and efficiency to the BER pathway. In this review, we have summarized the reported BER proteinprotein interactions and protein post-translational modifications and discuss the impact on DNA repair capacity and complex formation.

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Regulation of Human Flap Endonuclease-1 Activity by Acetylation through the Transcriptional Coactivator p300

Cited by 151 publications

References 39 publications

Acetylation regulates DNA repair mechanisms in human cells

Acetylation regulates DNA repair mechanisms in human cells

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

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