Autoregulation of the Rsc4 Tandem Bromodomain by Gcn5 Acetylation

VanDemark, Andrew P.; Kasten, Margaret M.; Ferris, Elliott; Héroux, A.; Hill, Christopher P.; Cairns, Bradley R.

doi:10.1016/j.molcel.2007.08.018

Cited by 124 publications

(150 citation statements)

References 39 publications

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“…9) and yeast remodeling protein Rsc4 (ref. 22). As seen by structural comparisons, the PHD finger and bromodomain in BPTF do not contact each other, but they are connected by a rigid threeturn α-helix that spans about 18 Å (Fig.…”

Section: Structural Integration Of the Phd Finger-bromodomainmentioning

confidence: 93%

“…Integrated functions in histone interactions have also been shown for tandem modules of the same fold, such as the double bromodomain in human transcriptional proteins BRD2 and BRD4 (ref. 20,21) and Rsc4 of the yeast RSC remodeling complex 22 , the double chromodomain of Drosophila melanogaster CHD1 (chromo-ATPase/helicase-DNA binding) 23 and the double Tudor domain of JMJD2A 24 . However, although tandem modules of different structural folds such as the PHD finger and the bromodomain are found in many transcriptional proteins 25,26 , molecular mechanisms for their possible interactive functions are much less understood.…”

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confidence: 99%

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Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

Zeng

Yap

Ivanov

et al. 2008

Nat Struct Mol Biol

118

117

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The tandem PHD finger-bromodomain, found in many chromatin-associated proteins, has an important role in gene silencing by the human co-repressor KRAB-associated protein 1 (KAP1). Here we report the three-dimensional solution structure of the tandem PHD finger-bromodomain of KAP1. The structure reveals a distinct scaffold unifying the two protein modules, in which the first helix, α Z , of an atypical bromodomain forms the central hydrophobic core that anchors the other three helices of the bromodomain on one side and the zinc binding PHD finger on the other. A comprehensive mutation-based structure-function analysis correlating transcriptional repression, ubiquitin-conjugating enzyme 9 (UBC9) binding and SUMOylation shows that the PHD finger and the bromodomain of KAP1 cooperate as one functional unit to facilitate lysine SUMOylation, which is required for KAP1 co-repressor activity in gene silencing. These results demonstrate a previously unknown unified function for the tandem PHD finger-bromodomain as an intramolecular small ubiquitin-like modifier (SUMO) E3 ligase for transcriptional silencing.Chemical modifications of chromatin on the DNA (for example, methylation of cytosine) and DNA-packing histones (for example, acetylation, methylation, phosphorylation, ubiquitination and SUMOylation) are important in the epigenetic control of gene transcription in response to physiological and environmental stimuli [1][2][3] . An emerging model suggests that there is an 'epigenetic code' embedded within chromatin to signify regions of distinct nuclear activities, such as heterochromatin formation or transcriptional activation [4][5][6] . It is thought that the epigenetic code is established by chromatin-modifying enzymes and interpreted by proteins that bind the chromatin in a modification-sensitive manner. The discovery of methyl-CpG binding domains 7 , bromodomains as acetyllysine binding The tandem bromodomain-PHD finger of the human transcriptional coactivator p300/CBP has been shown to be interdependent in interactions with nucleosomes 27 . A more common, reversely connected motif, the PHD finger-bromodomain, is found in many chromatinassociated proteins including histone lysine methyl-transferase MLL1 (ref. 28), Williams syndrome transcription factor (WSTF) in the chromatin-remodeling complex WINAC 29 , and the TIF1 family proteins (α, β, γ and δ; note that TIF1β is also known as KAP1 or TRIM28) 30 . This tandem PHD finger-bromodomain is also found in Sp140, a leukocytespecific protein in the nuclear body that is involved in the pathogenesis of acute promyelocytic leukemia and viral infection 31 . Mutations of PHD fingers, particularly those that disrupt zinc coordination, have been linked to tumor formation and genetic disorders 32 .More recently, it has been reported that the PHD finger of the human co-repressor KAP1 functions as a unique SUMO E3 ligase that is required for KAP1's gene transcription repression activity 33 .To understand its molecular function in gene silencing, we solved the three-dim...

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Section: Structural Integration Of the Phd Finger-bromodomainmentioning

confidence: 93%

mentioning

confidence: 99%

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

Zeng

Yap

Ivanov

et al. 2008

Nat Struct Mol Biol

118

117

View full text Add to dashboard Cite

show abstract

“…The Rsc4 subunit of the SWI/SNF-type remodeler RSC contains tandem bromodomains one of which binds H3K14ac. Remarkably, the adjacent bromodomain is able to bind acetylated lysine 25 of Rsc4 itself (VanDemark et al 2007). …”

Section: Regulation Of Remodelers By Posttranslational Modificationmentioning

confidence: 99%

“…Gcn5 is responsible for acetylation of both H3K14 and Rsc4K25, and hence, has the ability to promote RSC association with nucleosomes through H3 acetylation or inhibit RSC association with nucleosomes through Rsc4 acetylation (VanDemark et al 2007). These opposing reactions may serve to fine-tune the local activity of remodeling enzyme.…”

Section: Regulation Of Remodelers By Posttranslational Modificationmentioning

confidence: 99%

Nucleosome Remodeling and Epigenetics

Becker

Workman

2013

Cold Spring Harbor Perspectives in Biology

272

203

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“…The RSC ATP-dependent chromatin remodelling complex also contains bromodomains in the Sth1, Rsc1, Rsc2 and Rsc4 subunits, and is localised in an acetylation-dependent manner to gene coding sequences where it regulates histone and Pol II occupancy [16,30]. Interestingly, the tandem bromodomains within the RSC4 subunit have been biochemically shown to preferentially bind H4K14ac [31]. Furthermore, the central ATPase of the human Swi-Snf (BAF) chromatin remodelling complex contains a bromodomain that also shows specificity for H3K14ac, highlighting the potential importance of this mark upon ATP-dependent chromatin remodelling complex recruitment [32].…”

Section: How Could Histone Acetylation Promote Histone Eviction?mentioning

confidence: 99%