The Tale of Protein Lysine Acetylation in the Cytoplasm

Sadoul, Karin; Wang, Jin; Diagouraga, Boubou; Khochbin, Saadi

doi:10.1155/2011/970382

Cited by 131 publications

(135 citation statements)

References 169 publications

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“…[43][44][45][46] Several studies have provided evidence that a new leucine-rich NES created by the NPMc þ mutation promotes CRM1-dependent nuclear export of NPMc þ , thus resulting in accumulation of NPMc þ in the cytoplasm. [5][6][7]47,48 In the current study, we demonstrate that the redox-sensitive C288 generated by the NPMc þ mutation has an important role in regulating the cytoplasmic accumulation of NPMc þ .…”

Section: Discussionmentioning

confidence: 99%

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

Huang

Thomas

et al. 2013

Leukemia

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Mutations in exon 12 of the nucleophosmin (NPM1) gene (NPMc þ (NPM1 COOH terminal mutations)) define a distinct subset of acute myelogenous leukemias (AMLs), in which the NPMc þ protein localizes aberrantly to the leukemic cell cytoplasm. We have found that introduction of the most common NPMc þ variant into K562 and 32D cells sensitizes these cells to apoptosis induced by drugs such as bortezomib and arsenic trioxide (ATO) that induce reactive oxygen species (ROS) formation, and that cytotoxicity is prevented in the presence of N-acetyl-L-cysteine (NAC), an ROS scavenger. The substitution of tryptophan 288 (W288) by cysteine occurs in the great majority of NPM1c þ mutations. Mutagenesis of cysteine 288 to alanine re-localizes NPMc þ from the cytoplasm to the nucleolus and attenuates the sensitivity of cells expressing this mutation to bortezomib and ATO. Primary AML cells expressing NPMc þ are also significantly more sensitive than other AML cells to apoptosis induced by both drugs at pharmacologically achievable doses. We conclude that the presence of a cysteine moiety at position 288 results in the cytoplasmic localization of NPM1c þ and the increased sensitivity to bortezomib and ATO. These data suggest that bortezomib and ATO may have increased therapeutic efficacy in NPM1c þ leukemias.

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Section: Discussionmentioning

confidence: 99%

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

Huang

Thomas

et al. 2013

Leukemia

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“…At least three subunits of TFIIIC (TFIIIC110 and TFIIIC90) harbor HAT activity in vitro [26]. However, this classification should be reconsidered, as several nuclear HATs exhibit nuclear cytoplasmic shuttling, and cytoplasmic lysine acetylation has been associated with important physiological outcomes [27].…”

Section: Families Of Hatsmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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“…Currently, acetylation is recognized as a major post-translational modification of non-histone proteins modulating different biological processes such as gene expression, cell proliferation, cell survival and apoptosis. [1][2][3] The importance of this protein modification is emphasized by the fact that some cancers are associated with deregulated acetylation of lysine residues in histones, transcription factors or in critical regulatory proteins, such as tumor suppressor p53 or proto-oncogene Ras. [4][5][6][7] Whereas the influence of acetylation on the structure of chromatin has been well defined, recent studies indicate that acetylation also regulates activity of DNA repair proteins.…”

Section: Introductionmentioning

confidence: 99%

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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The Tale of Protein Lysine Acetylation in the Cytoplasm

Cited by 131 publications

References 169 publications

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

Role of cysteine 288 in nucleophosmin cytoplasmic mutations: sensitization to toxicity induced by arsenic trioxide and bortezomib

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Acetylation regulates DNA repair mechanisms in human cells

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