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

McCullagh, Paul; Chaplin, Tracy; Meerabux, Joanne; Grenzelias, Demetrios; Lillington, Debra M.; Poulsom, Richard; Gregorini, Armando; Saha, Vaskar; Young, Bryan D.

doi:10.1038/sj.onc.1203117

Cited by 20 publications

(31 citation statements)

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“…BRD1 contains a bromodomain, a plant homeodomain (PHD) finger, four potential binding sites for nuclear receptors and four predicted nuclear localization signals. 30 Additionally, we have also identified a PWWP-domain (proline-tryptophan-tryptophan-proline) which is approximately 70 amino acids in length and is believed to interact nonspecifically with DNA. 40 Bromodomains are found in a variety of mammalian, invertebrate and yeast DNA-binding proteins, and are able to interact with acetylated lysine on histone proteins.…”

Section: Discussionmentioning

confidence: 97%

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Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

et al. 2006

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Linkage studies suggest that chromosome 22q12-13 may contain one or more shared susceptibility genes for schizophrenia (SZ) and bipolar affective disorder (BPD). In a Faeroese sample, we previously reported association between microsatellite markers located at 22q13.31-qtel and both disorders. The present study reports an association analysis across five genes (including 14 single nucleotide and two microsatellite polymorphisms) in this interval using a case-control sample of 162 BPD, 103 SZ patients and 200 controls. The bromodomain-containing 1 gene (BRD1), which encodes a putative regulator of transcription showed association with both disorders with minimal P-values of 0.0046 and 0.00001 for single marker and overall haplotype analysis, respectively. A specific BRD1 2-marker 'risk' haplotype showed a frequency of B10% in the combined case group versus B1% in controls (P-value 2.8 Â 10 À7 ). Expression analysis of BRD1 mRNA revealed widespread expression in mammalian brain tissue, which was substantiated by immunohistochemical detection of BRD1 protein in the nucleus, perikaryal cytosol and proximal dendrites of the neurons in the adult rat, rabbit and human CNS. Quantitative mRNA analysis in developing fetal pig brain revealed spatiotemporal differences with high expression at early embryonic stages, with intense nuclear and cytosolar immunohistochemical staining of the neuroepithelial layer and early neuroblasts, whilst more mature neurons at later embryonic stages had less nuclear staining. The results implicate BRD1 with SZ and BPD susceptibility and provide evidence that suggests a role for BRD1 in neurodevelopment.

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Section: Discussionmentioning

confidence: 97%

“…30 It was raised against the 11 amino acid peptide RRPFSWEDVDR corresponding to amino acids 692-702 of BRD1.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

et al. 2006

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“…The other subunits of the MOZ/MORF complexes are EAF6 (homolog of yeast Esa1-associated factor 6) and BRPF1, -2, or -3 (bromodomain-PHD finger protein 1, 2, or 3). BRPF1 and BRPF2 are also known as BR140 (bromodomain protein of 140 kDa) and BRD1 (bromodomain protein 1), respectively (37,65). By using an analogy to the Esa1 and TIP60 complexes (19), we postulated that different subunits of MOZ/MORF complexes regulate the acetyltransferase activity (18).…”

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confidence: 99%

Molecular Architecture of Quartet MOZ/MORF Histone Acetyltransferase Complexes

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Pelletier

Xiao

et al. 2008

Molecular and Cellular Biology

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The monocytic leukemia zinc finger protein MOZ and the related factor MORF form tetrameric complexes with ING5 (inhibitor of growth 5), EAF6 (Esa1-associated factor 6 ortholog), and the bromodomain-PHD finger protein BRPF1, -2, or -3. To gain new insights into the structure, function, and regulation of these complexes, we reconstituted them and performed various molecular analyses. We found that BRPF proteins bridge the association of MOZ and MORF with ING5 and EAF6. An N-terminal region of BRPF1 interacts with the acetyltransferases; the enhancer of polycomb (EPc) homology domain in the middle part binds to ING5 and EAF6. The association of BRPF1 with EAF6 is weak, but ING5 increases the affinity. These three proteins form a trimeric core that is conserved from Drosophila melanogaster to humans, although authentic orthologs of The gene of MOZ (monocytic leukemia zinc finger protein, also referred to as MYST3 and KAT6A), located on chromosome 8p11, was first identified as a fusion partner in chromosome translocation t(8;16)(p11;p13) (2, 52). This recurrent translocation is associated with a monocytic subtype of acute myeloid leukemia and results in the fusion of the MOZ Nterminal domain to the C-terminal part of the transcription coactivator CBP. Two other leukemia-associated chromosomal rearrangements lead to the expression of proteins fusing MOZ fragments to the CBP paralog p300 and the p300/CBP-interacting nuclear receptor coactivator TIF2 (transcription intermediary factor 2, also known as steroid receptor coactivator 2 [SRC-2] and nuclear receptor coactivator 2 [NCOA2]) (6,8,29,34). One of the resulting fusion proteins, MOZ-TIF2, is known to promote self-renewal of leukemic stem cells (17,25), suggesting that the chromosome abnormalities play a causal role in leukemogenesis. In addition, it was recently reported that MOZ is fused to NCOA3 (22), a TIF2 paralog synonymous with SRC-3 and AIB1 (amplified in breast cancer 1). MOZ is highly homologous to MORF (MOZ-related factors, also named Querkopf, MYST4, and KAT6B) (11,64). The MORF gene is rearranged in leukemia patients with t(10; 16)(q22;p13) (46) and in leiomyoma cases with t(10;17)(p11; q21) (40). The CBP gene is the fusion partner in the former translocation, while the GCN5 gene is a potential candidate in the latter translocation. All of these findings suggest that deregulated acetylation has an important role in oncogenesis. In addition, recent studies indicate that MOZ and MORF play key roles in hematopoiesis, skeletogenesis, neurogenesis, and other developmental processes (16,26,38,39,62,64). Therefore, MOZ and MORF are intimately linked to both normal development and cancer development (63,69).At the molecular level, available data suggest that this pair of paralogs functions as transcriptional coactivators with intrinsic histone acetyltransferase (HAT) activity (3,11,12,27,28,48). Both possess the MYST domain, a catalytic core conserved among members of the MYST family of acetyltransferases (2, 52). Within this family, there are five members in hu...

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“…25 Two members of this family are involved in myeloid leukemia-associated rearrangements, namely MLL-MLLT6 and MLL-MLLT10. 26,27 However, the respective chimeric proteins differ considerably from PAX5-BRD1 in that the conserved PHD domains of MLLT6 and MLLT10 are lost, whereas the entire BRD1 protein is fused to PAX5.…”

Section: Discussionmentioning

confidence: 99%

Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia

et al. 2008

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PAX5, a master regulator of B-cell development, was recently shown to be involved in several leukemia-associated rearrangements, which result in fusion genes encoding chimeric proteins that antagonize PAX5 transcriptional activity. In a population-based fluorescence in situ hybridization screening study of 446 childhood acute lymphoblastic leukemia (ALL) patients, we now show that PAX5 rearrangements occur at an incidence of about 2.5% of B-cell precursor ALL. Identification of several novel PAX5 partner genes, including POM121, BRD1, DACH1, HIPK1 and JAK2 brings the number of distinct PAX5 inframe fusions to at least 12. Our data show that these not only comprise transcription factors but also structural proteins and genes involved in signal transduction, which at least in part have not been implicated in tumorigenesis.

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

Cited by 20 publications

References 56 publications

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

Molecular Architecture of Quartet MOZ/MORF Histone Acetyltransferase Complexes

Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia

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