AF4 uses the SL1 components of RNAP1 machinery to initiate MLL fusion- and AEP-dependent transcription.
AF4 uses the SL1 components of RNAP1 machinery to initiate MLL fusion- and AEP-dependent transcription.
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DOI：
10.1038/ncomms9869
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发表时间：
2015-11-23
影响因子：
16.6
通讯作者：
Yokoyama A
中科院分区：
文献类型：
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作者：
Okuda H;Kanai A;Ito S;Matsui H;Yokoyama A
基因重排产生MLL融合基因，这可能导致侵袭性白血病。在大多数情况下，MLL与编码AEP(AF4家族/enL家族/P-TEFb)共激活复合体的一个成分的基因融合。MLL-AEP融合蛋白通过结构性激活其靶基因使造血祖细胞永生化。在这里，我们证明了AEP和MLL-AEP融合蛋白通过选择性因子1(SL1)激活转录，选择性因子1是RNA聚合酶I(RNAP1)的预起始复合体(PIC)的核心成分。AF4家族蛋白的pSER结构域与染色质上的SL1结合，将TATA结合蛋白(TBP)加载到启动子上，启动依赖于RNA聚合酶II(RNAP2)的转录。这些结果揭示了一种先前未知的涉及AEP的转录启动机制，以及SL1作为TBP加载因子在RNAP2依赖的基因激活中的作用。MLL与AEP(AF4家族/ENL家族/P-TEFb)的蛋白融合可结构性激活其靶基因，使造血祖细胞永生化。在这里，Okuda等人。结果表明，MLL-AEP与RNA聚合酶(RNAP)I的预起始复合体的一个组成部分SL1结合，启动RNAP II依赖的转录。
Gene rearrangements generate MLL fusion genes, which can lead to aggressive leukemia. In most cases, MLL fuses with a gene encoding a component of the AEP (AF4 family/ENL family/P-TEFb) coactivator complex. MLL–AEP fusion proteins constitutively activate their target genes to immortalize haematopoietic progenitors. Here we show that AEP and MLL–AEP fusion proteins activate transcription through selectivity factor 1 (SL1), a core component of the pre-initiation complex (PIC) of RNA polymerase I (RNAP1). The pSER domain of AF4 family proteins associates with SL1 on chromatin and loads TATA-binding protein (TBP) onto the promoter to initiate RNA polymerase II (RNAP2)-dependent transcription. These results reveal a previously unknown transcription initiation mechanism involving AEP and a role for SL1 as a TBP-loading factor in RNAP2-dependent gene activation. Protein fusions between MLL and AEP (AF4 family/ENL family/P-TEFb) constitutively activate their target genes to immortalize hematopoietic progenitors. Here, Okuda et al. show that MLL-AEP binds SL1, a component of the pre-initiation complex of RNA polymerase (RNAP) I, to initiate RNAP II dependent transcription.