The Human Replicative Helicase, the CMG Complex, as a Target for Anti-cancer Therapy.
The Human Replicative Helicase, the CMG Complex, as a Target for Anti-cancer Therapy.
复制标题
DOI：
10.3389/fmolb.2018.00026
复制
发表时间：
2018
影响因子：
5
通讯作者：
Kang YH
中科院分区：
文献类型：
--
作者：
Seo YS;Kang YH
DNA解旋酶在复制、重组和修复过程中解开或重排双链DNA。许多病原体如病毒、细菌和原生动物的解旋酶已被研究为治疗感染性疾病的潜在靶点，而人类DNA解旋酶则是抗癌治疗的潜在靶点。DNA复制机器在每个细胞周期中执行复制基因组的基本任务，而DNA解旋酶是这些机器的重要功能之一。复制型解旋酶通常是多亚单位的蛋白质复合体，作为真核复制型解旋酶活性的最小复合体由11个亚基组成，需要两个亚复合体和一个蛋白质的功能组装。异六聚体MCM2-7解旋酶通过与CDC45和异源四聚体GINS形成络合物--CDC45-McM2-7-GINS(CMG)而被激活。CMG复合体可以成为治疗癌症的潜在靶点，最近已经测试了这种复制解旋酶作为治疗靶点的可行性。已经实施了几种不同的策略，并正在积极研究以干扰CMG复合体的解旋酶活性。本文根据相关文献对CMG解旋酶在DNA复制过程中的分子功能及其与癌症的相关性进行了综述。此外，还总结了目前在寻找抑制CMG解旋酶的小分子以开发抗癌治疗策略方面所做的努力，为进一步发现CMG靶向药物提供了新的视角。
DNA helicases unwind or rearrange duplex DNA during replication, recombination and repair. Helicases of many pathogenic organisms such as viruses, bacteria, and protozoa have been studied as potential therapeutic targets to treat infectious diseases, and human DNA helicases as potential targets for anti-cancer therapy. DNA replication machineries perform essential tasks duplicating genome in every cell cycle, and one of the important functions of these machineries are played by DNA helicases. Replicative helicases are usually multi-subunit protein complexes, and the minimal complex active as eukaryotic replicative helicase is composed of 11 subunits, requiring a functional assembly of two subcomplexes and one protein. The hetero-hexameric MCM2-7 helicase is activated by forming a complex with Cdc45 and the hetero-tetrameric GINS complex; the Cdc45-Mcm2-7-GINS (CMG) complex. The CMG complex can be a potential target for a treatment of cancer and the feasibility of this replicative helicase as a therapeutic target has been tested recently. Several different strategies have been implemented and are under active investigations to interfere with helicase activity of the CMG complex. This review focuses on the molecular function of the CMG helicase during DNA replication and its relevance to cancers based on data published in the literature. In addition, current efforts made to identify small molecules inhibiting the CMG helicase to develop anti-cancer therapeutic strategies were summarized, with new perspectives to advance the discovery of the CMG-targeting drugs.