TBP loading by AF4 through SL1 is the major rate-limiting step in MLL fusion-dependent transcription
TBP loading by AF4 through SL1 is the major rate-limiting step in MLL fusion-dependent transcription
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DOI：
10.1080/15384101.2016.1222337
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发表时间：
2016-01-01
期刊：
影响因子：
4.3
通讯作者：
Yokoyama, Akihiko
中科院分区：
文献类型：
--
作者：
Okuda, Hiroshi;Takahashi, Satoshi;Yokoyama, Akihiko
混合谱系白血病(MLL)基因重排通过诱导正常只在未成熟造血祖细胞中表达的基因亚群的组成性表达而导致白血病。MLL基因重排通常产生MLL与AF4家族/enL家族/P-TEFb(AEP)复合体的一个组分的融合产物。MLL-AEP融合蛋白具有成分募集P-TEFb延长复合体的潜力。因此，假设解除RNA聚合酶II启动子近端的暂停是MLL融合依赖转录的限速步骤。AEP还有可能通过MED26招募调解人复合体。我们最近发现，AEP通过SL1复合体促进TBP负载到TATA元件，从而激活转录启动。在本研究中，我们证明了MLL-AEP融合蛋白致癌特性的关键活性是TBP负载活性，而不是介体募集或转录延伸活性。因此，我们认为AF4通过SL1装载TBP是MLL融合依赖转录的主要限速步骤。
Gene rearrangement of the mixed lineage leukemia (MLL) gene causes leukemia by inducing the constitutive expression of a gene subset normally expressed only in the immature haematopoietic progenitor cells. MLL gene rearrangements often generate fusion products of MLL and a component of the AF4 family/ENL family/P-TEFb (AEP) complex. MLL-AEP fusion proteins have the potential of constitutively recruiting the P-TEFb elongation complex. Thus, it is hypothesized that relieving the promoter proximal pausing of RNA polymerase II is the rate-limiting step of MLL fusion-dependent transcription. AEP also has the potential to recruit the mediator complex via MED26. We recently showed that AEP activates transcription initiation by facilitating TBP loading to the TATA element through the SL1 complex. In the present study, we show that the key activity responsible for the oncogenic property of MLL-AEP fusion proteins is the TBP loading activity, and not the mediator recruitment or transcriptional elongation activities. Thus, we propose that TBP loading by AF4 through SL1 is the major rate-limiting step in MLL fusion-dependent transcription.