5afw

Assembly of methylated LSD1 and CHD1 drives AR-dependent transcription and translocation

spinqualitylabelsall models 5afw, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5afw is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CL, EDO, MLY Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CHD1_HUMAN ATP-dependent chromatin-remodeling factor which functions as substrate recognition component of the transcription regulatory histone acetylation (HAT) complex SAGA. Regulates polymerase II transcription. Also required for efficient transcription by RNA polymerase I, and more specifically the polymerase I transcription termination step. Regulates negatively DNA replication. Not only involved in transcription-related chromatin-remodeling, but also required to maintain a specific chromatin configuration across the genome. Is also associated with histone deacetylase (HDAC) activity (By similarity). Required for the bridging of SNF2, the FACT complex, the PAF complex as well as the U2 snRNP complex to H3K4me3. Functions to modulate the efficiency of pre-mRNA splicing in part through physical bridging of spliceosomal components to H3K4me3. Required for maintaining open chromatin and pluripotency in embryonic stem cells. Publication Abstract from PubMed Prostate cancer evolution is driven by a combination of epigenetic and genetic alterations such as coordinated chromosomal rearrangements, termed chromoplexy. TMPRSS2-ERG gene fusions found in human prostate tumors are a hallmark of chromoplexy. TMPRSS2-ERG fusions have been linked to androgen signaling and depend on androgen receptor (AR)-coupled gene transcription. Here, we show that dimethylation of KDM1A at K114 (to form K114me2) by the histone methyltransferase EHMT2 is a key event controlling androgen-dependent gene transcription and TMPRSS2-ERG fusion. We identified CHD1 as a KDM1A K114me2 reader and characterized the KDM1A K114me2-CHD1 recognition mode by solving the cocrystal structure. Genome-wide analyses revealed chromatin colocalization of KDM1A K114me2, CHD1 and AR in prostate tumor cells. Together, our data link the assembly of methylated KDM1A and CHD1 with AR-dependent transcription and genomic translocations, thereby providing mechanistic insight into the formation of TMPRSS2-ERG gene fusions during prostate-tumor evolution. Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation.,Metzger E, Willmann D, McMillan J, Forne I, Metzger P, Gerhardt S, Petroll K, von Maessenhausen A, Urban S, Schott AK, Espejo A, Eberlin A, Wohlwend D, Schule KM, Schleicher M, Perner S, Bedford MT, Jung M, Dengjel J, Flaig R, Imhof A, Einsle O, Schule R Nat Struct Mol Biol. 2016 Jan 11. doi: 10.1038/nsmb.3153. PMID:26751641 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Chromodomain-helicase-DNA-binding protein 3D structures

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