PHD Domain-Mediated E3 Ligase Activity Directs Intramolecular Sumoylation of an Adjacent Bromodomain Required for Gene Silencing

Ivanov, Alexey V.; Peng, Hongzhuang; Yurchenko, Vyacheslav; Yap, Kyoko L.; Negorev, Dmitri; Schultz, D.; Psulkowski, Elyse; Fredericks, William J.; White, David E.; Maul, Gerd G.; Sadofsky, Moshe J.; Zhou, Ming; Rauscher, Frank J.

doi:10.1016/j.molcel.2007.11.012

Cited by 362 publications

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“…Unlike other SUMO E3 ligases-such as the RING/U-box and HECT domain E3s 39 , which commonly function to bring together an activated E2 SUMO and a substrate to promote SUMO conjugation-the KAP1 PHD finger-bromodomain is an intramolecular SUMO E3 ligase, thus ensuring ordered and stoichiometric site-specific SUMOylation at several lysine residues within the bromodomain and in the region N-terminal to the PHD finger, which together are required for KAP1's co-repression activity 33,41,42 .…”

Section: Discussionmentioning

confidence: 99%

“…Because of the large size of SUMO, lysine 33 . Although, as shown in our in vitro study, the KAP1 PHD finger and the bromodomain do not interact with methylated lysine, acetylated lysine or even unmodified histone peptides (consistent with its lack of key residues required for such interactions), the tandem PHD finger-bromodomain may function uniquely as an integrated structural template.…”

Section: Discussionmentioning

confidence: 99%

“…4a,b online), and that the PHD finger of KAP1 functions as a SUMO E3 ligase for KAP1 SUMOylation 33 . Of six SUMOylation sites mapped in KAP1, four reside within the PHD finger-bromodomain unit (Fig.…”

Section: Sumoylation and Binding Of The Kap1 Tandem Domain To Ubc9mentioning

confidence: 99%

“…Of six SUMOylation sites mapped in KAP1, four reside within the PHD finger-bromodomain unit (Fig. 4) and two in a region N-terminal to the PHD finger 33 . Using an in vitro SUMOylation assay and lysine-to-arginine mutations of the PHD finger- bromodomain, we showed that two major SUMOylation sites are located at Lys779 in the BC loop and Lys804 in the loop following α C of the bromodomain ( Supplementary Fig.…”

mentioning

confidence: 99%

“…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 .…”

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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

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Sumoylation and Binding Of The Kap1 Tandem Domain To Ubc9mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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

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112

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Role of genome guardian proteins in transcriptional elongation

Bunch

2016

FEBS Letters

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Edited by Ivan SadowskiMaintaining genomic integrity is vital for cell survival and homeostasis. Mutations in critical genes in germ-line and somatic cells are often implicated with the onset or progression of diseases. DNA repair enzymes thus take important roles as guardians of the genome in the cell. Besides the known function to repair DNA damage, recent findings indicate that DNA repair enzymes regulate the transcription of protein-coding and noncoding RNA genes. In particular, a novel role of DNA damage response signaling has been identified in the regulation of transcriptional elongation. Topoisomerasesmediated DNA breaks appear important for the regulation. In this review, recent findings of these DNA break-and repair-associated enzymes in transcription and potential roles of transcriptional activation-coupled DNA breaks are discussed.

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Chromatin Recognition Protein Modules: The PHD Finger

Lallous

Ramón‐Maiques

2011

Encyclopedia of Life Sciences

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The structure of chromatin controls the accessibility to deoxyribonucleic acid (DNA) information. Posttranslational modifications (PTMs) of histones modify the architecture of chromatin and provide docking platforms for proteins that control many DNA‐templated processes. The plant homeodomain (PHD) fingers are small protein domains found in nuclear factors that interact with chromatin. Recent studies have characterised two classes among the PHD fingers, which specifically bind to either unmodified or trimethylated K4 histone H3. A number of PHD finger structures in complex with histone peptides reveal the recognition mechanisms. The combination of multiple histone PTMs, the cooperation between different PHD fingers or between PHD fingers and other histone recognition proteins illustrate the plurality and versatility of this protein module. Mutations or translocations in PHD fingers that affect their interaction with histones have been related to immunological diseases, cancer or mental retardation. Key Concepts: Histone modifications form part of the chromatin control of DNA‐templated processes. PHD fingers are small nuclear protein domains that bind two zinc ions in an interlaced topology. Several PHD fingers specifically recognise the di‐ and trimethylated K4 histone H3 tail, and others bind specifically to unmethylated K4 histone H3. Aromatic cages are cavities formed by the side chains of 2–4 aromatic residues used by PHD fingers and by other protein modules for binding to methylated lysines. Alterations of the histone recognition by PHD fingers are related to immunological diseases, cancer and mental retardation.

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PHD Domain-Mediated E3 Ligase Activity Directs Intramolecular Sumoylation of an Adjacent Bromodomain Required for Gene Silencing

Cited by 362 publications

References 38 publications

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

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

Role of genome guardian proteins in transcriptional elongation

Chromatin Recognition Protein Modules: The PHD Finger

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