Okuda Hiroshi, Kanai Akinori, Ito Shinji, Matsui Hirotaka, Yokoyama Akihiko
Laboratory for Malignancy Control Research, Kyoto University Graduate School of Medicine, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8501, Japan.
Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Nat Commun. 2015 Nov 23;6:8869. doi: 10.1038/ncomms9869.
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.
基因重排会产生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）共激活复合物一个组分的基因融合。MLL-AEP融合蛋白持续激活其靶基因，从而使造血祖细胞永生化。我们在此表明，AEP和MLL-AEP融合蛋白通过选择性因子1（SL1）激活转录，SL1是RNA聚合酶I（RNAP1）起始前复合物（PIC）的核心组分。AF4家族蛋白的pSER结构域在染色质上与SL1结合，并将TATA结合蛋白（TBP）加载到启动子上，以启动RNA聚合酶II（RNAP2）依赖性转录。这些结果揭示了一种以前未知的涉及AEP的转录起始机制，以及SL1作为RNAP2依赖性基因激活中TBP加载因子的作用。
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