The bromodomain: a conserved sequence found in human,<i>Drosophila</i>and yeast proteins

Haynes, Susan R.; Dollard, Catherine; Winston, Fred; Beck, Stephan; Trowsdale, John; Dawid, Igor B.

doi:10.1093/nar/20.10.2603

Cited by 370 publications

(348 citation statements)

References 8 publications

(3 reference statements)

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“…This motif was ®rst described following the cloning of the brahma (brm) gene in drosophila (Haynes et al, 1992;Tamkun et al, 1992) and has since been identi®ed in other transcriptional co-activators including the human brahma protein, BRM (Muchardt and Yaniv, 1993) and the yeast protein SNF2/SWI2 (Laurent et al, 1993). The cell cycle gene 1 (CCG1) (Sekiguchi et al, 1991) which was later identi®ed as hTAF II 250 (Hisatake et al, 1993;Ruppert et al, 1993) and shown to be necessary for G1 progression in mammalian cells also contains a bromodomain.…”

Section: Discussionmentioning

confidence: 99%

“…More than one bromodomain can be present within a protein: polybromo, a gene of unknown function isolated from chicken monoblasts, encodes a putative protein with ®ve bromodomains (Nicolas and Goodwin, 1996). The bromodomain was originally described as a sequence of about 60 amino acids, potentially forming two a-helices (Haynes et al, 1992). However this motif has recently been rede®ned (Jeanmougin et al, 1997) extending to approximately 110 residues with two additional a-helices, each on either side of the two existing helices.…”

Section: Discussionmentioning

confidence: 99%

“…It has, however, been shown by several groups that the bromodomain is dispensable for HAT activity Mizzen, 1996 #77;Ogryzko, 1996 #76). It may provide a surface for protein-protein contacts (Haynes et al, 1992) and it has been suggested that it has a role in directing HAT activity to chromatin`receptors' . Studies of the binding of p300 to the activating transcription factor-2 (ATF-2) have highlighted the importance of the bromodomain of p300 (Kawasaki et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

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The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

McCullagh¹,

Chaplin²,

Meerabux³

et al. 1999

Oncogene

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The MLL gene is reciprocally translocated with one of a number of di erent partner genes in a proportion of human acute leukaemias. The precise mechanism of oncogenic transformation is unclear since most of the partner genes encode unrelated proteins. However, two partner genes, AF10 and AF17 are related through the presence of a cysteine rich region and a leucine zipper. The identi®cation of other proteins with these structures will aid our understanding of their role in normal and leukaemic cells. We report the cloning of a novel human gene (BRL) which encodes a protein containing a cysteine rich region related to that of AF10 and AF17 and is overall most closely related to the previously known protein BR140. BRL maps to chromosome 22q13 and shows high levels of expression in testis and several cell lines. The deduced protein sequence also contains a bromodomain, four potential LXXLL motifs and four predicted nuclear localization signals. A monoclonal antibody raised to a BRL peptide sequence con®rmed its widespread expression as a 120 Kd protein and demonstrated localization to the nucleus within spermatocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

McCullagh¹,

Chaplin²,

Meerabux³

et al. 1999

Oncogene

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“…For example, methylation of histone H3K9 provides an epigenetic mark for the binding of the chromodomain (protein domain structure that binds methylated lysine) containing protein, HP1 (heterochromatin protein 1), that leads to heterochromatin formation and gene repression [15]. In contrast, acetylation of histones tends to decrease interaction between histones and DNA, and facilitates binding of bromodomain (protein domain structure that binds acetylated lysine) containing proteins, thereby promoting an open chromatin conformation suitable for transcriptional activation [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Plant SET domain-containing proteins: Structure, function and regulation

Wang

Chandrasekharan

et al. 2007

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

176

195

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Modification of the histone proteins that form the core around which chromosomal DNA is looped has profound epigenetic effects on the accessibility of the associated DNA for transcription, replication and repair. The SET domain is now recognized as generally having methyltransferase activity targeted to specific lysine residues of histone H3 or H4. There is considerable sequence conservation within the SET domain and within its flanking regions. Previous reviews have shown that SET proteins from Arabidopsis and maize fall into five classes according to their sequence and domain architectures. These classes generally reflect specificity for a particular substrate. SET proteins from rice were found to fall into similar groupings, strengthening the merit of the approach taken. Two additional classes, VI and VII, were established that include proteins with truncated/ interrupted SET domains. Diverse mechanisms are involved in shaping the function and regulation of SET proteins. These include protein-protein interactions through both intra-and inter-molecular associations that are important in plant developmental processes, such as flowering time control and embryogenesis. Alternative splicing that can result in the generation of two to several different transcript isoforms is now known to be widespread. An exciting and tantalizing question is whether, or how, this alternative splicing affects gene function. For example, it is conceivable that one isoform may debilitate methyltransferase function whereas the other may enhance it, providing an opportunity for differential regulation. The review concludes with the speculation that modulation of SET protein function is mediated by antisense or sense-antisense RNA.

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“…Targeted histone acetylation could contribute to promoter activation by changing or disrupting the repressive chromatin structure (31,47). The bromodomain also would be retained, which is thought to be important in protein-protein interactions as well as modulation of chromatin because of its conservation in the SWI͞SNF2 complex, that appears to modulate the chromatin of the genes it regulates (48,49). All of these functions would be brought to the amino terminal portion of MLL, that presumably would retain its ability to bind AT-rich DNA, perhaps redirecting the chromatin modification and coadaptor functions of CBP to inappropriate genomic regions.…”

Section: Discussionmentioning

confidence: 99%

MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3)

Sobulo

Borrow

Tomek

et al. 1997

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

303

158

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A BSTR ACTThe recurring translocation t(11;16)-(q23;p13.3) has been documented only in cases of acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase II. We show that the MLL gene is fused to the gene that codes for CBP (CREB-binding protein), the protein that binds specifically to the DNAbinding protein CREB (cAMP response element-binding protein) in this translocation. MLL is fused in-frame to a different exon of CBP in two patients producing chimeric proteins containing the AT-hooks, methyltransferase homology domain, and transcriptional repression domain of MLL fused to the CREB binding domain or to the bromodomain of CBP. Both fusion products retain the histone acetyltransferase domain of CBP and may lead to leukemia by promoting histone acetylation of genomic regions targeted by the MLL AT-hooks, leading to transcriptional deregulation via aberrant chromatin organization. CBP is the first partner gene of MLL containing well defined structural and functional motifs that provide unique insights into the potential mechanisms by which these translocations contribute to leukemogenesis.The t(11;16)(q23;p13.3) is a rare recurring translocation that has been described in 11 patients to date (1). All of these patients have therapy-related acute leukemia of myeloid or lymphoid phenotype, or myelodysplasia, after exposure to DNA topoisomerase II inhibitors (anthracyclines or epipodophyllotoxins) for treatment of a primary malignancy.MLL (also called ALL1, Htrx, and HRX; refs. 2-6), which is located on chromosomal band 11q23, is involved in translocations with at least 40 different partner genes (7-9). These translocations result in acute leukemia, either lymphoblastic or myeloid͞monocytic, with a close correlation between the specific translocation and a particular leukemia phenotype. MLL also is involved in translocations that occur secondary to therapy of a primary malignant disease with drugs that target DNA topoisomerase II and result in therapy-related acute myeloid leukemia or acute lymphoblastic leukemia (10-14). The t(11;16)(q23;p13.3) occurs only in therapy-related leukemia or myelodysplasia, in contrast to other MLL translocations such as the t(9;11), t(4;11), or t(11;19), which are seen primarily in de novo leukemia with no more than about 5-10% having leukemia occurring after treatment.MLL codes for a very large protein, with a predicted molecular mass of 431 kDa (4-6). The protein contains several domains identified by homology to other proteins or by functional analysis. Three AT-hook DNA-binding domains near the amino terminus also are found in the high-mobility group proteins HMG-I(Y) (15). MLL contains a region of homology to mammalian DNA methyltransferases, transcriptional activation and repression domains, and a cysteine-rich region that forms three C4HC3 zinc fingers [plant homeodomain (PHD) or leukemia-associated-protein domains] (16-21). The PHD domain and the SET [Su(var)3-9 enhancer of zeste, and trithorax] domain at the carboxyl terminus are the regions...

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The bromodomain: a conserved sequence found in human,Drosophilaand yeast proteins

Cited by 370 publications

References 8 publications

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

The cloning, mapping and expression of a novel gene, BRL, related to the AF10 leukaemia gene

Plant SET domain-containing proteins: Structure, function and regulation

MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3)

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