Phosphorylation of MLL by ATR is required for execution of mammalian S-phase checkpoint.
Phosphorylation of MLL by ATR is required for execution of mammalian S-phase checkpoint.
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作者：
实施细胞周期检查点以保护基因组，避免遗传错误的积累。检查点丢失导致基因组不稳定，并有助于癌症的演变。在G1-、S-、G2-和M-期检查点中，遗传研究表明完整的S-期检查点在维持基因组完整性中的作用。虽然多细胞生物中S期检查点的基本框架已经被概述，但机制细节仍有待阐明。人类染色体11带q23易位破坏MLL基因导致预后不良的白血病，。在这里，我们指定MLL作为哺乳动物S期检查点网络中的一种新型效应器，并将检查点功能障碍确定为MLL白血病的潜在机制。MLL在丝氨酸516处被ATR磷酸化以响应S期的遗传毒性应激，这破坏了其与SCFSkp 2 E3连接酶的相互作用，因此破坏了其被SCFSkp 2 E3连接酶降解，导致其积累。稳定的MLL蛋白在染色质上积累，在晚期复制起点甲基化组蛋白H3赖氨酸4，并抑制CDC 45的加载以延迟DNA复制。缺乏MLL的细胞表现出辐射抗性DNA合成和染色单体型基因组异常，表明S期检查点功能障碍。用野生型而非S516 A或ΔSET突变型MLL重建Mll −/−（Mll也称为Mll 1）小鼠胚胎成纤维细胞可挽救S期检查点缺陷。此外，携带模拟人t（11;16）白血病的M11-CBP敲入等位基因的鼠骨髓祖细胞显示出严重的放射抗性DNA合成表型。MLL融合体作为显性负突变体发挥作用，其消除了ATR介导的野生型MLL对DNA损伤的磷酸化/稳定化，从而损害了S期检查点。总之，我们的研究结果确定MLL作为哺乳动物DNA损伤反应途径的一个关键组成部分，并表明MLL易位引起的S期检查点的失调可能有助于人类MLL白血病的发病机制。
Cell cycle checkpoints are implemented to safeguard the genome, avoiding the accumulation of genetic errors,. Checkpoint loss results in genomic instability and contributes to the evolution of cancer. Among G1-, S-, G2- and M-phase checkpoints, genetic studies indicate the role of an intact S-phase checkpoint in maintaining genome integrity,. Although the basic framework of the S-phase checkpoint in multicellular organisms has been outlined, the mechanistic details remain to be elucidated. Human chromosome-11 band-q23 translocations disrupting theMLLgene lead to poor prognostic leukaemias,,,,. Here we assign MLL as a novel effector in the mammalian S-phase checkpoint network and identify checkpoint dysfunction as an underlying mechanism of MLL leukaemias. MLL is phosphorylated at serine 516 by ATR in response to genotoxic stress in the S phase, which disrupts its interaction with, and hence its degradation by, the SCFSkp2E3 ligase, leading to its accumulation. Stabilized MLL protein accumulates on chromatin, methylates histone H3 lysine 4 at late replication origins and inhibits the loading of CDC45 to delay DNA replication. Cells deficient in MLL showed radioresistant DNA synthesis and chromatid-type genomic abnormalities, indicative of S-phase checkpoint dysfunction. Reconstitution ofMll−/−(Mllalso known asMll1) mouse embryonic fibroblasts with wild-type but not S516A or ΔSET mutant MLL rescues the S-phase checkpoint defects. Moreover, murine myeloid progenitor cells carrying anMll–CBPknock-in allele that mimics human t(11;16) leukaemia show a severe radioresistant DNA synthesis phenotype. MLL fusions function as dominant negative mutants that abrogate the ATR-mediated phosphorylation/stabilization of wild-type MLL on damage to DNA, and thus compromise the S-phase checkpoint. Together, our results identify MLL as a key constituent of the mammalian DNA damage response pathway and show that deregulation of the S-phase checkpoint incurred by MLL translocations probably contributes to the pathogenesis of human MLL leukaemias.
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影响因子：
11.4
作者：
Meyer, C.;Kowarz, E.;Marschalek, R.
通讯作者：
Marschalek, R.
影响因子：
5.3
作者：
Hsieh, JJD;Ernst, P;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
16
作者：
Milne, TA;Briggs, SD;Hess, JL
通讯作者：
Hess, JL
DOI：
10.1073/pnas.0408836102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Milne, TA;Hughes, CM;Hess, JL
通讯作者：
Hess, JL
影响因子：
64.8
作者：
Lim, DS;Kim, ST;Kastan, MB
通讯作者：
Kastan, MB