Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.
Biomed Pharmacother. 2021 Apr;136:111190. doi: 10.1016/j.biopha.2020.111190. Epub 2021 Jan 23.
Eukaryotic chromosomal DNA replication is preceded by replication licensing which involves the identification of the origin of replication by origin recognition complex (ORC). The ORC loads pre-replication complexes (pre-RCs) through a series of tightly regulated mechanisms where the ORC interacts with Cdc6 to recruit cdt1-MCM2-7 complexes to the origin of replication. In eukaryotes, adherence to regulatory mechanisms of the replication program is required to ensure that all daughter cells carry the exact copy of genetic material as the parent cell. Failure of which leads to the development of genome instability syndromes like cancer, diabetes, etc. In an event of such occurrence, preventing cells from carrying the defaulted genetic material and passing it to other cells hinges on the regulation of chromosomal DNA replication. Thus, understanding the mechanisms underpinning chromosomal DNA replication and particularly replication licensing can expose druggable enzymes, effector molecules, and secondary messengers that can be targeted for diagnosis and therapeutic purposes. Effectively drugging these molecular markers to reprogram pre-replication events can be used to control the fate of chromosomal DNA replication for the treatment of genome instability disorders and in this case, cancer. This review discusses available knowledge of replication licensing in the contest of molecular drug discovery for the treatment of cancer.
真核生物染色体 DNA 的复制是在复制许可的前提下进行的，其中涉及到复制起始复合物（ORC）识别复制起始点。ORC 通过一系列严格调控的机制加载前复制复合物（pre-RC），在此过程中，ORC 与 Cdc6 相互作用，将 cdt1-MCM2-7 复合物招募到复制起始点。在真核生物中，为了确保所有子细胞都携带与母细胞完全相同的遗传物质，必须遵守复制程序的调控机制。否则，会导致基因组不稳定性综合征的发生，如癌症、糖尿病等。为了防止细胞携带有缺陷的遗传物质并将其传递给其他细胞，可以通过调节染色体 DNA 复制来实现。因此，深入了解染色体 DNA 复制的机制，特别是复制许可，有助于发现可作为诊断和治疗靶点的药物靶标酶、效应分子和第二信使。通过有效靶向这些分子标记物来重新编程前复制事件，可以用于控制染色体 DNA 复制的命运，从而治疗基因组不稳定性疾病，在这种情况下，就是癌症。本文综述了在癌症治疗的分子药物发现背景下，关于复制许可的相关知识。
