Structure and function of RNA polymerase II elongation factor ELL. Identification of two overlapping ELL functional domains that govern its interaction with polymerase and the ternary elongation complex.
The human ELL gene on chromosome 19p13.1 undergoes frequent translocations with the trithorax-like MLL gene on chromosome 11q23 in acute myeloid leukemia. Recently, the human ELL gene was shown to encode an RNA polymerase II elongation factor that activates elongation by suppressing transient pausing by polymerase at many sites along the DNA. In this report, we identify and characterize two overlapping ELL functional domains that govern its interaction with RNA polymerase II and the ternary elongation complex. Our findings reveal that, in addition to its elongation activation domain, ELL contains a novel type of RNA polymerase II interaction domain that is capable of negatively regulating polymerase activity in promoter-specific transcription initiation in vitro. Notably, the MLL-ELL translocation results in deletion of a portion of this functional domain, and ELL mutants lacking sequences deleted by the translocation bind RNA polymerase II and are fully active in elongation, but fail to inhibit initiation. Taken together, these results raise the possibility that the MLL-ELL translocation could alter ELL-RNA polymerase II interactions that are not involved in regulation of elongation.
Shilatifard
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A
Program in Molecular and Cell Biology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
Haque
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D
Conaway
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Conaway
J W
JW
D002888:Chromosomes, Human, Pair 19; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D010441:Peptide Chain Elongation, Translational; D010445:Peptide Elongation Factors; D011401:Promoter Regions, Genetic; D011519:Proto-Oncogenes; D012319:RNA Polymerase II / Q000378:metabolism*; D035581:Transcription Factor TFIIB; D035362:Transcription Factor TFIID; D014157:Transcription Factors / Q000378:metabolism*; D019473:Transcription Factors, TFII / Q000378:metabolism; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C090862:ELL protein, human; C497422:KMT2A protein, human; D009363:Neoplasm Proteins; D010445:Peptide Elongation Factors; D035581:Transcription Factor TFIIB; D035362:Transcription Factor TFIID; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D012319:RNA Polymerase II