Structural and Functional Conservation of the NuA4 Histone Acetyltransferase Complex from Yeast to Humans

Doyon, Yannick; Selleck, William; Lane, William S.; Tan, Song; Côté, Jacques

doi:10.1128/mcb.24.5.1884-1896.2004

Cited by 531 publications

(564 citation statements)

References 65 publications

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“…EPC2 is a member of the polycomb protein family, involved in heterochromatin formation. 25 This family of highly conserved proteins seems to be directly involved in essential epigenetic events governing both transcriptional activation and repression. 26 Other examples of genes associated with MR and epigenetic regulation are JARID1C, MECP2, CDKL5 and EHMT1.…”

Section: Discussionmentioning

confidence: 99%

The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype

et al. 2009

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Section: Discussionmentioning

confidence: 99%

The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype

et al. 2009

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“…The majority of ATM is soluble (Ͼ90% (21), implying that the majority of ATM exists in association with Tip60. Tip60 is the HAT component of the NuA4 complex (13,22), which contains the ATM homologue TRRAP. Although several protein components of NuA4 have been implicated in DNA repair (14,23), ATM has not been identified as a component of the NuA4 complex (22).…”

Section: Resultsmentioning

confidence: 99%

“…Tip60 is the HAT component of the NuA4 complex (13,22), which contains the ATM homologue TRRAP. Although several protein components of NuA4 have been implicated in DNA repair (14,23), ATM has not been identified as a component of the NuA4 complex (22). To determine whether NuA4 and ATM constitute distinct Tip60 complexes, cell extracts were immunoprecipitated with antibodies to either ATM or TRRAP.…”

Section: Resultsmentioning

confidence: 99%

A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM

Sun

Jiang

Chen

et al. 2005

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

649

658

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FATC domain ͉ TRRAP ͉ NuA4 ͉ chromatin remodeling T he product of the ataxia telangiectasia (AT) gene, the AT mutant (ATM) protein kinase, is a key component of the signal-transduction pathway activated by DNA damage (1). In response to DNA strand breaks, ATM's kinase activity is upregulated, and ATM becomes autophosphorylated on Ser 1981 (2). ATM autophosphorylation initiates the conversion of the inactive ATM dimer to an active, monomeric ATM. ATM then phosphorylates multiple proteins involved in the DNA damage response, including nbs1, p53, chk2, and SMC1 (1, 3). These phosphorylated proteins, in turn, regulate the two key responses to DNA damage: the activation of cell-cycle checkpoints and the initiation of DNA repair.Although the downstream signaling pathways activated by ATM are well characterized, the mechanism by which DNA strand breaks are detected and how this leads to activation of ATM's kinase activity are less clear. The Mre11͞Rad50͞Nbs1 (MRN) complex, a DNA-binding complex involved in the detection and repair of DNA damage, may play a role in regulating ATM activity. MRN functions as an adaptor protein that links activated ATM with its target proteins [including chk2 (4) and SMC1 (3)] to allow productive phosphorylation (5, 6). Biochemical studies have shown that the DNA-dependent activation of ATM's kinase activity requires the functional MRN complex (7,8). However, although several studies have demonstrated that activation of ATM's kinase activity in cells lacking functional MRN complex is reduced (6, 9), other studies have shown that ATM activation is relatively normal in MRN-defective cells (5, 10). Furthermore, other proteins, including the p18 tumorsuppressor protein (11), have been shown to participate in ATM activation. Thus, although the MRN complex may regulate ATM activation under certain conditions, additional protein factors may also be required for ATM activation in vivo.Recent studies have shown that the repair of DNA doublestrand breaks requires the remodeling of chromatin structure (12-14). Furthermore, ATM can be activated by changes in chromatin structure that occur independently of DNA damage (2), leading to the proposal that ATM activation is mediated by alterations in chromatin structure at sites of DNA damage rather than through direct activation of ATM by strand breaks (1, 2). Chromatin remodeling is linked to the posttranslational modification of histones through phosphorylation, methylation, and acetylation (15). Histone acetyltransferases (HATs) can acetylate both histones and several nonhistone proteins (13,15). Here, we examined whether Tip60, a HAT previously implicated in the DNA-damage response, provides the link between DNA strand breaks in chromatin and the activation of ATM. The results indicate that DNA damage induces rapid acetylation of ATM by a mechanism that depends on the Tip60 HAT. Suppression of Tip60 blocks activation of ATM's kinase activity and sensitizes cells to ionizing radiation (IR). Furthermore, the FATC domain of ATM mediates the interaction bet...

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“…These studies provide evidence that TRRAP/Tra1/trr1/ Nipped-A plays an essential role in development, although its involvement in different pathways during embryogenesis remains to be elucidated. Because TRRAP is highly conserved through evolution Vassilev et al, 1998) and given structural and functional conservation of TRRAP-containing HAT complexes from yeast to humans (Doyon et al, 2004), it is likely that TRRAP regulates the same pathways and processes during development in different organisms across the evolutionary tree.…”

Section: Essential Function Of Trrap In Embryonic Developmentmentioning

confidence: 99%

Orchestration of chromatin-based processes: mind the TRRAP

et al. 2007

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Chromatin modifications at core histones including acetylation, methylation, phosphorylation and ubiquitination play an important role in diverse biological processes. Acetylation of specific lysine residues within the N terminus tails of core histones is arguably the most studied histone modification; however, its precise roles in different cellular processes and how it is disrupted in human diseases remain poorly understood. In the last decade, a number of histone acetyltransferases (HATs) enzymes responsible for histone acetylation, has been identified and functional studies have begun to unravel their biological functions. The activity of many HATs is dependent on HAT complexes, the multiprotein assemblies that contain one HAT catalytic subunit, adapter proteins, several other molecules of unknown function and a large protein called TRansformation/tRanscription domain-Associated Protein (TRRAP). As a common component of many HAT complexes, TRRAP appears to be responsible for the recruitment of these complexes to chromatin during transcription, replication and DNA repair. Recent studies have shed new light on the role of TRRAP in HAT complexes as well as mechanisms by which it mediates diverse cellular processes. Thus, TRRAP appears to be responsible for a concerted and context-dependent recruitment of HATs and coordination of distinct chromatin-based processes, suggesting that its deregulation may contribute to diseases. In this review, we summarize recent developments in our understanding of the function of TRRAP and TRRAP-containing HAT complexes in normal cellular processes and speculate on the mechanism underlying abnormal events that may lead to human diseases such as cancer.

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Structural and Functional Conservation of the NuA4 Histone Acetyltransferase Complex from Yeast to Humans

Cited by 531 publications

References 65 publications

The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype

The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype

A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM

Orchestration of chromatin-based processes: mind the TRRAP

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