A chromosomal SIR2 homologue with both histone NAD-dependent ADP-ribosyltransferase and deacetylase activities is involved in DNA repair in Trypanosoma brucei

García‐Salcedo, José A.

doi:10.1093/emboj/cdg553

Cited by 122 publications

(159 citation statements)

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“…TbSIR2RP1, a SIR2-related protein from the protozoan parasite Trypanosoma brucei, has been shown to catalyze the mono(ADP)-ribosylation of histones, particulary H2A and H2B, and treatment of trypanosomal nuclei with a DNA alkylating agent results in a significant increase in the level of histone H2A/H2B ADP-ribosylation. Consequently, depletion of TbSIR2RP1 decreased the cellular resistance to DNA damage (Garcia-Salcedo et al, 2003). However, histone ADP-ribosylation occurs only upon DNA single-srand break, and its role in double-strand break repair is not clear now.…”

Section: Othersmentioning

confidence: 99%

Histone modifications in DNA damage response

Cao

Shen

Zhu

2016

Sci. China Life Sci.

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DNA damage is a relatively common event in eukaryotic cell and may lead to genetic mutation and even cancer. DNA damage induces cellular responses that enable the cell either to repair the damaged DNA or cope with the damage in an appropriate way. Histone proteins are also the fundamental building blocks of eukaryotic chromatin besides DNA, and many types of post-translational modifications often occur on tails of histones. Although the function of these modifications has remained elusive, there is ever-growing studies suggest that histone modifications play vital roles in several chromatin-based processes, such as DNA damage response. In this review, we will discuss the main histone modifications, and their functions in DNA damage response.DNA damage response, histone modifications, chromatin, DNA repair Citation:

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Section: Othersmentioning

confidence: 99%

Histone modifications in DNA damage response

Cao

Shen

Zhu

2016

Sci. China Life Sci.

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“…However, after the introduction of DNA damage, these proteins are relocalized from the telomeres to DNA repair sites (75,76), resulting in derepression of genes normally silenced by telomere position effect (77). A SIR2 homologue has been described recently in T. brucei (78) that plays a role in DNA repair and is enriched at telomeres. Although it appears unlikely that the telomere position effect plays a central role in ES down-regulation in bloodstream form T. brucei, one scenario is that the accumulation of stalled replication forks or DNA damage results in the relocalization of limiting silencing factors, resulting in derepression.…”

Section: Up-regulation Of Silent Ess Correlates With a Block In Smentioning

confidence: 99%

Bloodstream Form-specific Up-regulation of Silent VSG Expression Sites and Procyclin in Trypanosoma brucei after Inhibition of DNA Synthesis or DNA Damage

Sheader

Vruchte

Rudenko

2004

Journal of Biological Chemistry

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The African trypanosome Trypanosoma brucei transcribes the active variant surface glycoprotein (VSG) gene from one of about 20 VSG expression sites (ESs). In order to study ES control, we made reporter lines with a green fluorescent protein gene inserted behind the promoter of different ESs. We attempted to disrupt the silencing machinery, and we used fluorescence-activated cell sorter analysis for the rapid and sensitive detection of ES up-regulation. We find that a range of treatments that either block nuclear DNA synthesis, like aphidicolin, or modify DNA-like cisplatin and 1-methyl-3-nitro-1-nitrosoguanidine results in up-regulation of silent ESs. Aphidicolin treatment was the most effective, with almost 80% of the cells expressing green fluorescent protein from a silent ES. All of these treatments blocked the cells in S phase. In contrast, a range of toxic chemicals had little or no effect on expression. These included berenil and pentamidine, which selectively cleave the mitochondrial kinetoplast DNA, the metabolic inhibitors suramin and difluoromethylornithine, and the mitotic inhibitor rhizoxin. Up-regulation also affected other RNA polymerase I (pol I) transcription units, as procyclin genes were also up-regulated after cells were treated with either aphidicolin or DNA-modifying agents. Strikingly, this up-regulation of silent pol I transcription units was bloodstream form-specific and was not observed in insect form T. brucei. We postulate that the redistribution of a limiting bloodstream form-specific factor involved in both silencing and DNA repair results in the derepression of normally silenced pol I transcription units after DNA damage.

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“…Recently, SIRT6 was demonstrated to be a nuclear ADP-ribosyltransferase (18), whereas a T. brucei SIR2 homologue exhibited both histone NAD-dependent ADP-ribosyltransferase and deacetylase activities (19). These observations indicate that sirtuins can function either as NAD-dependent protein deacetylases or as ribosyltransferases.…”

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Regulation of Insulin Secretion by SIRT4, a Mitochondrial ADP-ribosyltransferase

Ahuja

Schwer

Carobbio

et al. 2007

Journal of Biological Chemistry

367

355

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Sirtuins are homologues of the yeast transcriptional repressor Sir2p and are conserved from bacteria to humans. We report that human SIRT4 is localized to the mitochondria. SIRT4 is a matrix protein and becomes cleaved at amino acid 28 after import into mitochondria. Mass spectrometry analysis of proteins that coimmunoprecipitate with SIRT4 identified insulindegrading enzyme and the ADP/ATP carrier proteins, ANT2 and ANT3. SIRT4 exhibits no histone deacetylase activity but functions as an efficient ADP-ribosyltransferase on histones and bovine serum albumin. SIRT4 is expressed in islets of Langerhans and colocalizes with insulin-expressing ␤ cells. Depletion of SIRT4 from insulin-producing INS-1E cells results in increased insulin secretion in response to glucose. These observations define a new role for mitochondrial SIRT4 in the regulation of insulin secretion.Histone deacetylases are enzymes that catalyze the removal of acetyl groups from the ⑀-amino group of lysine residues and are separated into three classes. Sirtuins, the class III histone deacetylases, are homologous to the yeast transcriptional repressor, Sir2p, and are NAD ϩ -dependent enzymes (1-3). Seven sirtuins have been identified in the human genome (4, 5). They share a conserved Sir2 catalytic core domain and exhibit variable amino-and carboxyl-terminal extensions that contribute to their unique subcellular localization and may also regulate their catalytic activity.The subcellular distribution, substrate specificity, and cellular functions of sirtuins are quite diverse (reviewed in Refs. 1-3). SIRT1 is found in the nucleus, where it functions as a transcriptional repressor via histone deacetylation. SIRT1 can also regulate transcription by modifying the acetylation levels of transcription factors, such as MyoD, FOXO, p53, and NF-B (6 -12). The SIRT2 protein is found in the cytoplasm, where it associates with microtubules and deacetylates lysine 40 of ␣-tubulin (13). The SIRT3 protein is localized in the mitochondrial matrix (14, 15), where it is proteolytically processed at its NH 2 terminus, yielding a mature protein that has protein deacetylase activity (14). These observations indicate that the targets of sirtuins are not restricted to histone proteins but extend to acetylated proteins in other subcellular compartments.Sirtuins also differ in their substrate specificities. For instance, SIRT1, -2, and -3 have robust activity on chemically acetylated histone H4 peptides, whereas SIRT5 has weak but detectable activity, and SIRT4, -6, and -7 have no detectable activity on the same substrate (13). Interestingly, a sirtuin from Archaeoglobus fulgidus, Sir2-Af1, which has close homology with SIRT5, also has weak activity on a histone peptide but significantly stronger activity on an acetylated bovine serum albumin substrate (16,17). Similarly, both SIRT1 and SIRT2 can deacetylate p53; however, only SIRT2 deacetylates lysine 40 of ␣-tubulin (13, 17).Recently, SIRT6 was demonstrated to be a nuclear ADP-ribosyltransferase (18), whereas a T. brucei SI...

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A chromosomal SIR2 homologue with both histone NAD-dependent ADP-ribosyltransferase and deacetylase activities is involved in DNA repair in Trypanosoma brucei

Cited by 122 publications

References 82 publications

Histone modifications in DNA damage response

Histone modifications in DNA damage response

Bloodstream Form-specific Up-regulation of Silent VSG Expression Sites and Procyclin in Trypanosoma brucei after Inhibition of DNA Synthesis or DNA Damage

Regulation of Insulin Secretion by SIRT4, a Mitochondrial ADP-ribosyltransferase

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