Nasheuer, H.P.; Meaney, A.M. Starting DNA Synthesis: Initiation Processes during the Replication of Chromosomal DNA in Humans. Genes2024, 15, 360.
Nasheuer, H.P.; Meaney, A.M. Starting DNA Synthesis: Initiation Processes during the Replication of Chromosomal DNA in Humans. Genes 2024, 15, 360.
Nasheuer, H.P.; Meaney, A.M. Starting DNA Synthesis: Initiation Processes during the Replication of Chromosomal DNA in Humans. Genes2024, 15, 360.
Nasheuer, H.P.; Meaney, A.M. Starting DNA Synthesis: Initiation Processes during the Replication of Chromosomal DNA in Humans. Genes 2024, 15, 360.
Abstract
The initiation reactions of DNA synthesis are central processes during human chromosomal DNA replication. They are separated into two main processes: the initiation events at replication origins, the start of the leading strand synthesis for each replicon, and the numerous initiation events taking place during lagging strand DNA synthesis. In addition, a third mechanism is the re-initiation of DNA synthesis after replication fork stalling, which takes place when DNA lesions hinder the progression of DNA synthesis. The initiation of leading strand synthesis at replication origin is regulated at multiple levels, from the origin recognition to the assembly and activation of replicative helicase, the Cdc45-MCM2-7-GINS (CMG) complex. In addition, the multiple interactions of the CMG complex with the eukaryotic replicative DNA polymerases such as DNA polymerase α-primase (Pol α), DNA polymerase δ and ε at replication forks play pivotal roles in the mechanism of initiation reactions including the initiation of signalling unperturbed and stalled replication forks, ‘replication stress’ events, via ATR (ATM-Rad 3-related protein kinase). All these processes are essential for the accurate transfer of the cells’ genetic information to their daughters. Failures and dysfunctions in these processes gives rise to genome instability followed by genetic diseases including cancer. Thus, in their review ‘Hallmarks of Cancer: New Dimensions‘ Hanahan and Weinberg (2022) called genome instability a fundamental function in the development process of cancer cells. In recent years, the understanding of the initiation processes and mechanisms of human DNA replication has made substantial progress at all levels which will be discussed in the review.
Keywords
DNA replication; origin of replication; initiation; replication fork; Okazaki fragment; DNA damage signalling; ATR kinase; telomeres
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
