Collaboration of MLLT1/ENL, Polycomb and ATM for transcription and genome integrity
Collaboration of MLLT1/ENL, Polycomb and ATM for transcription and genome integrity
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DOI：
10.1080/19491034.2016.1177681
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发表时间：
2016-04
期刊：
影响因子：
3.7
通讯作者：
A. Ui;A. Yasui
中科院分区：
文献类型：
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作者：
A. Ui;A. Yasui
摘要 Polycomb 组 (PcG) 抑制转录，而 Trithorax 组 (TrxG) 激活组织发育和细胞增殖的转录，这些因子的失调通常与癌症相关。 ENL (MLLT1) 和 AF9 (MLLT3) 是混合谱系白血病 (MLL)、TrxG 蛋白的融合伴侣，也是超级延伸复合体 (SEC) 的因子。 SEC 控制转录延伸以释放 RNA 聚合酶 II，在转录起始位点附近暂停。在 MLL 重排白血病中，已发现 SEC 的多种成分作为 MLL 融合伴侣，并且转录延伸的控制被错误调节，导致 MLL-SEC 融合白血病中的肿瘤发生。有人提出，ENL/AF9-MLL 和 PcG 的意外协作参与了白血病的肿瘤发生。最近，我们发现 ENL/AF9 和 PcG 的合作导致了一种在 ATM 信号下从延伸到抑制的转录转换的新机制，以保证基因组完整性。激活的 ATM 在 SEC 中磷酸化 ENL/AF9，磷酸化的 ENL/AF9 结合 BMI1 和 RING1B（多梳抑制复合物 1 (PRC1) 中的异二聚体 E3-泛素-连接酶复合物），并在转录延伸位点招募 PRC1 以快速抑制转录。 SEC 和 PcG 介导的转录抑制中的 ENL/AF9 促进转录位点附近的 DSB 修复。这意味着 SEC 和 PcG 中 ENL/AF9 的协作确保了转录从延伸到抑制的快速响应，以实现 DSB 修复的邻近基因毒性应激。因此，这些结果表明，ENL/AF9 和 PcG 在转录控制中的协作是维持基因组完整性所必需的，并且可能与 MLL-ENL/AF9 白血病有关。
SUMMARY Polycomb group (PcG) repress, whereas Trithorax group (TrxG) activate transcription for tissue development and cellular proliferation, and misregulation of these factors is often associated with cancer. ENL (MLLT1) and AF9 (MLLT3) are fusion partners of Mixed Lineage Leukemia (MLL), TrxG proteins, and are factors in Super Elongation Complex (SEC). SEC controls transcriptional elongation to release RNA polymerase II, paused around transcription start site. In MLL rearranged leukemia, several components of SEC have been found as MLL-fusion partners and the control of transcriptional elongation is misregulated leading to tumorigenesis in MLL-SEC fused Leukemia. It has been suggested that unexpected collaboration of ENL/AF9-MLL and PcG are involved in tumorigenesis in leukemia. Recently, we found that the collaboration of ENL/AF9 and PcG led to a novel mechanism of transcriptional switch from elongation to repression under ATM-signaling for genome integrity. Activated ATM phosphorylates ENL/AF9 in SEC, and the phosphorylated ENL/AF9 binds BMI1 and RING1B, a heterodimeric E3-ubiquitin-ligase complex in Polycomb Repressive complex 1 (PRC1), and recruits PRC1 at transcriptional elongation sites to rapidly repress transcription. The ENL/AF9 in SEC- and PcG-mediated transcriptional repression promotes DSB repair near transcription sites. The implication of this is that the collaboration of ENL/AF9 in SEC and PcG ensures a rapid response of transcriptional switching from elongation to repression to neighboring genotoxic stresses for DSB repair. Therefore, these results suggested that the collaboration of ENL/AF9 and PcG in transcriptional control is required to maintain genome integrity and may be link to the MLL-ENL/AF9 leukemia.