Mutation of cancer driver MLL2 results in transcription stress and genome instability.
Mutation of cancer driver MLL2 results in transcription stress and genome instability.
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癌症驱动器MLL2的突变导致转录应力和基因组不稳定性。
DOI：
10.1101/gad.275453.115
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发表时间：
2016-02-15
影响因子：
10.5
通讯作者：
Svejstrup JQ
中科院分区：
文献类型：
--
作者：
Kantidakis T;Saponaro M;Mitter R;Horswell S;Kranz A;Boeing S;Aygün O;Kelly GP;Matthews N;Stewart A;Stewart AF;Svejstrup JQ
在这项研究中，Kantidakis等人研究了MLL 2在肿瘤发生中的作用机制，发现MLL 2突变导致基因组不稳定。他们表明，MLL 2突变的细胞显示出大量转录应激的迹象，受影响最大的基因与早期复制的脆性位点重叠，显示出γ-H2 AX水平升高，并遭受频繁的突变。基因组不稳定性是肿瘤发生的一个反复出现的特征。编码组蛋白甲基转移酶的MLL 2突变是许多不同癌症类型的驱动因素，但其机制尚不清楚。在这里，我们提出的证据表明，MLL 2突变导致基因组不稳定性。可诱导MLL 2基因缺失的小鼠细胞显示姐妹染色单体交换、大体染色体畸变、53 BP 1病灶和微核水平升高。人MLL 2敲除细胞的特征也在于基因组不稳定性。有趣的是，MLL 2与RNA聚合酶II（RNAPII）和RECQL 5相互作用，尽管MLL 2突变的细胞在基因中具有正常的总体H3 K4 me水平，但紧邻RNAPII的核小体是低甲基化的。重要的是，MLL 2突变的细胞显示出大量转录应激的迹象，并且最受影响的基因与早期复制的脆性位点重叠，显示出γ H2 AX水平升高，并且遭受频繁的突变。MLL 2在基因中维持基因组稳定性的需要有助于解释其在癌症中的广泛作用，并指出转录应激是肿瘤发生的强大驱动因素。
In this study, Kantidakis et al. investigate the mechanism underlying the role of MLL2 in tumorigenesis and find that MLL2 mutation causes genome instability. They show that MLL2 mutated cells display signs of substantial transcription stress, and the most affected genes overlap with early replicating fragile sites, show elevated levels of γ-H2AX, and suffer frequent mutation. Genome instability is a recurring feature of tumorigenesis. Mutation in MLL2, encoding a histone methyltransferase, is a driver in numerous different cancer types, but the mechanism is unclear. Here, we present evidence that MLL2 mutation results in genome instability. Mouse cells in which MLL2 gene deletion can be induced display elevated levels of sister chromatid exchange, gross chromosomal aberrations, 53BP1 foci, and micronuclei. Human MLL2 knockout cells are characterized by genome instability as well. Interestingly, MLL2 interacts with RNA polymerase II (RNAPII) and RECQL5, and, although MLL2 mutated cells have normal overall H3K4me levels in genes, nucleosomes in the immediate vicinity of RNAPII are hypomethylated. Importantly, MLL2 mutated cells display signs of substantial transcription stress, and the most affected genes overlap with early replicating fragile sites, show elevated levels of γH2AX, and suffer frequent mutation. The requirement for MLL2 in the maintenance of genome stability in genes helps explain its widespread role in cancer and points to transcription stress as a strong driver in tumorigenesis.