The CMG helicase and cancer: a tumor "engine" and weakness with missing mutations.
The CMG helicase and cancer: a tumor "engine" and weakness with missing mutations.
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DOI：
10.1038/s41388-022-02572-8
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发表时间：
2023-02
期刊：
影响因子：
8
通讯作者：
Alexandrow, Mark G.
中科院分区：
文献类型：
--
作者：
Xiang, Shengyan;Reed, Damon R.;Alexandrow, Mark G.
复制性Cdc45-MCM-GINS （CMG）解旋酶是一种大型蛋白质复合物，在哺乳动物细胞DNA复制过程中，作为复制体的一个组成部分，在DNA融化和解绕步骤中起作用。尽管CMG在细胞生长中起着重要的作用，但CMG在细胞周期事件中并不是一个简单的旁观者。CMG的组成部分，特别是MCM前体，也参与通过调节DNA复制分叉速度来维持基因组稳定性，促进从复制应激中恢复，并防止随之而来的DNA损伤。鉴于这些重要功能，MCM/CMG复合物受到TGF-ß1等生长因子和Myc、Cyclin E和视网膜母细胞瘤蛋白（Rb）等信号因子的高度调控。当这些信号介质被解除调控，且肿瘤抑制蛋白p53缺失时，MCM/CMG复合物的管理不当会导致基因组不稳定性增加，并且是致瘤转化和肿瘤异质性的一个因素。本综述的目的是深入了解哺乳动物基因组中CMG在其组装和激活过程中受到调节的机制和动力学，以及由于致癌改变而导致的CMG调节错误如何促进肿瘤发生。最后，也是最重要的是，我们强调了对CMG解旋酶作为癌症治疗干预的可利用脆弱性和新靶点的新认识。
The replicative Cdc45-MCM-GINS (CMG) helicase is a large protein complex that functions in the DNA melting and unwinding steps as a component of replisomes during DNA replication in mammalian cells. Although the CMG performs this important role in cell growth, the CMG is not a simple bystander in cell cycle events. Components of the CMG, specifically the MCM precursors, are also involved in maintaining genomic stability by regulating DNA replication fork speeds, facilitating recovery from replicative stresses, and preventing consequential DNA damage. Given these important functions, MCM/CMG complexes are highly regulated by growth factors such as TGF-ß1 and by signaling factors such as Myc, Cyclin E, and the retinoblastoma protein (Rb). Mismanagement of MCM/CMG complexes when these signaling mediators are deregulated, and in the absence of the tumor suppressor protein p53, leads to increased genomic instability and is a contributor to tumorigenic transformation and tumor heterogeneity. The goal of this review is to provide insight into the mechanisms and dynamics by which the CMG is regulated during its assembly and activation in mammalian genomes, and how errors in CMG regulation due to oncogenic changes promote tumorigenesis. Finally, and most importantly, we highlight the emerging understanding of the CMG helicase as an exploitable vulnerability and novel target for therapeutic intervention in cancer.
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影响因子：
3.8
作者：
Tan DF;Huberman JA;Hyland A;Loewen GM;Brooks JS;Beck AF;Todorov IT;Bepler G
通讯作者：
Bepler G
影响因子：
19
作者：
Blow, JJ;Hodgson, B
通讯作者：
Hodgson, B
DOI：
10.1083/jcb.152.6.1267
发表时间：
2001-03-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Furstenthal L;Kaiser BK;Swanson C;Jackson PK
通讯作者：
Jackson PK
DOI：
10.1158/1541-7786.mcr-14-0464
发表时间：
2015-09
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Bryant VL;Elias RM;McCarthy SM;Yeatman TJ;Alexandrow MG
通讯作者：
Alexandrow MG
影响因子：
16
作者：
Botchan M;Berger J
通讯作者：
Berger J