The Drosophila trithorax proteins contain a novel variant of the nuclear receptor type DNA binding domain and an ancient conserved motif found in other chromosomal proteins

Stassen, M. Janna; Bailey, David A.; Nelson, Stephanie; Chinwalla, Vandana; Harte, Peter J.

doi:10.1016/0925-4773(95)00402-m

Cited by 137 publications

(126 citation statements)

References 80 publications

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“…This motif was originally discovered in Drosophila proteins Su(var)3-9, Enhancer-of-zeste and Trithorax, which are involved in variegated or developmental gene expression (6). Although a functional role for the SET domain was not immediately evident, limited homology with plant methyltransferases prompted the discovery that Su(var)3-9 and its Schizosaccharomyces pombe homolog CLR4 are capable of transferring a methyl group onto Lys-9 of histone H3 (2).…”

mentioning

confidence: 99%

A trithorax-group complex purified from Saccharomyces cerevisiae is required for methylation of histone H3

Nagy

Griesenbeck²,

Kornberg³

et al. 2001

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

299

276

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Histone methylation has emerged as an important mechanism for regulating the transcriptional accessibility of chromatin. Several methyltransferases have been shown to target histone aminoterminal tails and mark nucleosomes associated with either euchromatic or heterochromatic states. However, the biochemical machinery responsible for regulating histone methylation and integrating it with other cellular events has not been well characterized. We report here the purification, molecular identification, and genetic and biochemical characterization of the Set1 protein complex that is necessary for methylation of histone H3 at lysine residue 4 in Saccharomyces cerevisiae. The seven-member 363-kDa complex contains homologs of Drosophila melanogaster proteins Ash2 and Trithorax and Caenorhabditis elegans protein DPY-30, which are implicated in the maintenance of Hox gene expression and regulation of X chromosome dosage compensation, respectively. Mutations of Set1 protein comparable to those that disrupt developmental function of its Drosophila homolog Trithorax abrogate histone methylation in yeast. These studies suggest that epigenetic regulation of developmental and sex-specific gene expression are species-specific readouts for a common chromatin remodeling machinery associated mechanistically with histone methylation.C ovalent modification of histone amino-terminal tails regulates access to the underlying DNA and thus serves an important role in fine tuning gene expression (1). Histone modifications such as acetylation and phosphorylation facilitate transitions between chromatin states that are permissive or restrictive for transcription (2). More recently, histone methylation has emerged as an additional modification for recruitment of chromatin-associated proteins that determine transcriptional accessibility of genes. Several methyltransferases have been shown to target histone amino-terminal tails and mark nucleosomes associated with either euchromatic or heterochromatic states (3-5).A subset of methyltransferases contains a highly conserved motif known as the SET domain. This motif was originally discovered in Drosophila proteins Su(var)3-9, Enhancer-of-zeste and Trithorax, which are involved in variegated or developmental gene expression (6). Although a functional role for the SET domain was not immediately evident, limited homology with plant methyltransferases prompted the discovery that Su(var)3-9 and its Schizosaccharomyces pombe homolog CLR4 are capable of transferring a methyl group onto Lys-9 of histone H3 (2). This methyl tag has subsequently been shown to mark nucleosomes that are associated with transcriptionally silenced genes in the Sch. pombe mating type locus (7), and the association of Su-(var)3-9 homologs with the Rb corepressor complex suggests that Lys-9 methylation may also play a role in transcriptional repression of euchromatic genes (8).Human SET domain-containing proteins such as MLL, a homolog of Drosophila Trithorax, NSD2, and NSD3 are essential for normal development and are also direc...

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mentioning

confidence: 99%

A trithorax-group complex purified from Saccharomyces cerevisiae is required for methylation of histone H3

Nagy

Griesenbeck²,

Kornberg³

et al. 2001

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

299

276

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“…In MLL, fMLL, MT and PCM1, the consensus is clearly recognizable as a tandem repeat of CGXCX 2 C anked by basic amino acids. A very similar sequence is also present in TRX (CX 2 CX 2 SX 5 SX 2 SX 2 S) at amino acids 1238 ± 1256 (amino acid numbering based on sequence in Stassen et al, 1995) (Figure 4b) although this does not contain the MT consensus above. As Drosophila do not contain methylated DNA (Bird, 1995;Heniko and Matzke, 1997), this similarity may be fortuitous.…”

Section: Comparison Of Mll/trx Proteinsmentioning

confidence: 90%

“…The nuclear targeting sequences are also underscored with broken lines. Abbreviations: AThooks, AT-hook homologies with HMG-Y proteins (Gu et al, 1992;Tkachuk et al, 1992;Domer et al, 1993); TRX1, TRX2; two regions in human MLL with homology to the Drosophila trithorax protein (Domer et al, 1993); SPBR1 and SPBR2, SET protein binding regions 1 and 2 (Adler et al, 1997); NTS, Nuclear targeting signal ; SNL, speckled nuclear localization ; MT, DNA Methyltransferase domain (Ma et al, 1993); PHD, Zinc ®ngers originally described in two plant homeodomain proteins (Schindler et al, 1993;Aasland et al, 1995); ZNF, a diverged PHD Zinc Finger domain (Prasad et al, 1997); ATA1-2; two regions found in MLL and TRX not represented in other proteins (Stassen et al, 1995;Tillib et al, 1995;Prasad et al, 1997) , 1986). Nucleotide comparisons of the region encompassing the 11q23 breakpoint cluster of the human gene (spanning exons 5 ± 11) with the equivalent region of the Fugu gene (Table 1 and data not shown) reveals the conserved nature of exons 8, 9, and 10 which contain PHD ®ngers 1 and 2, but shows no obvious conserved features in the introns.…”

Section: Genomic Structure Of Fmllmentioning

confidence: 99%

“…Targeted disruption of the mouse Mll locus results in anterior and posterior homeotic transformations associated with abnormalities of Hox gene expression and this further supports the hypothesis that MLL/Mll are functional equivalents of trx . Two large regions of MLL show homology to TRX: a cluster of putative zinc-®nger structures (three PHD, one ZNF) and associated sequences (ATA1) in the middle of the protein, and the last 256 amino acids (ATA2 and the SET domain) (Gu et al, 1992;Tkachuk et al, 1992;Stassen et al, 1995;Prasad et al, 1997). Both the zinc-®nger and SET domains are shared by other proteins in Drosophila, as well as proteins in other species (Tschiersch et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

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Isolation and characterization of a Pufferfish MLL (Mixed lineage leukemia)-like gene (fMll) reveals evolutionary conservation in vertebrate genes related to Drosophila trithorax

et al. 1998

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The MLL gene is interrupted and fused to a number of partner genes as a result of chromosomal translocations in human leukemias. MLL is a very large protein with a unique domain structure and large regions of homology to Drosophila trx. To de®ne the key structural and functional domains of the MLL protein in vertebrates, we have cloned the genomic region encoding an MLLlike gene in the compact model vertebrate genome of Fugu rubripes. While the similarity between the mouse and human MLL proteins is very high, a lower overall similarity is present between the Fugu and mammalian proteins. Several new highly conserved regions were identi®ed in the portion of the protein included in the MLL leukemia-associated fusion proteins. The conserved nature of regions of similarity between vertebrate forms of MLL and the Drosophila TRX proteins, as well as other domains previously suggested to have a functional role in MLL (including the AT hooks and the DNA methyltransferase domain), was also observed. Therefore, strong evolutionary constraints limited sequence divergence within these domains. The information derived from this comparative analysis will form the basis for the functional study of the MLL protein, particularly as it relates to human leukemogenesis.

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“…As a consequence, the SYT-associated transcription transactivation machinery may be recruited to genes that are normally regulated by MLL. Through the MLL-AF10 fusion, MLL has lost its SET domain (Stassen et al, 1995;Tschiersch et al, 1994) and, thereby, its link to both the histone modifying SWI/SNF protein complex (Rozenblatt-Rosen et al, 1998) and the multimeric Polycomb group protein complex (Jenuwein et al, 1998;Tripoulas et al, 1996). Modulation of the activitities described in this model may come from the SYT-hmlg2 protein.…”

Section: Discussionmentioning

confidence: 99%

The synovial sarcoma associated protein SYT interacts with the acute leukemia associated protein AF10

Bruijn¹,

Santos²,

Thijssen³

et al. 2001

Oncogene

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As a result of the synovial sarcoma associated t(X;18) translocation, the human SYT gene on chromosome 18 is fused to either the SSX1 or the SSX2 gene on the X chromosome. Although preliminary evidence indicates that the (fusion) proteins encoded by these genes may play a role in transcriptional regulation, little is known about their exact function. We set out to isolate interacting proteins through yeast two hybrid screening of a human cDNA library using SYT as a bait. Of the positive clones isolated, two were found to correspond to the acute leukemia t(10;11) associated AF10 gene, a fusion partner of MLL. Con®rmation of these results was obtained via co-immunoprecipitation of endogenous and exogenous, epitope-tagged, SYT and AF10 proteins from cell line extracts and colocalization of epitopetagged SYT and AF10 proteins in transfected cells. Subsequent sequential mutation analysis revealed a highly speci®c interaction of N-terminal SYT fragments with C-terminal AF10 fragments. The N-terminal interaction domain of the SYT protein was also found to be present in several SYT orthologs and homologs. The C-terminal interaction domain of AF10 is located outside known functional domains. Based on these results, a model is proposed in which the SYT and AF10 proteins act in concert as bipartite transcription factors. This model has implications for the molecular mechanisms underlying the development of both human synovial sarcomas and acute leukemias. Oncogene (2001) 20, 3281 ± 3289.

show abstract

The Drosophila trithorax proteins contain a novel variant of the nuclear receptor type DNA binding domain and an ancient conserved motif found in other chromosomal proteins

Cited by 137 publications

References 80 publications

A trithorax-group complex purified from Saccharomyces cerevisiae is required for methylation of histone H3

A trithorax-group complex purified from Saccharomyces cerevisiae is required for methylation of histone H3

Isolation and characterization of a Pufferfish MLL (Mixed lineage leukemia)-like gene (fMll) reveals evolutionary conservation in vertebrate genes related to Drosophila trithorax

The synovial sarcoma associated protein SYT interacts with the acute leukemia associated protein AF10

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