Preparation for DNA replication: the key to a successful S phase

Abstract

Successful genome duplication is required for cell proliferation and demands extraordinary precision and accuracy. The mechanisms by which cells enter, progress through, and exit S phase are intense areas of focus in the cell cycle and genome stability fields. Key molecular events in the G1 phase of the cell division cycle, especially origin licensing, are essential for pre-establishing conditions for efficient DNA replication during the subsequent S phase. If G1 events are poorly regulated or disordered, then DNA replication can be compromised leading to genome instability, a hallmark of tumorigenesis. Upon entry into S phase, coordinated origin firing and replication progression ensure complete, timely, and precise chromosome replication. Both G1 and S phase progressions are controlled by master cell cycle protein kinases and ubiquitin ligases that govern the activity and abundance of DNA replication factors. In this short review, we describe current understanding and recent developments related to G1 progression and S phase entrance and exit with a particular focus on origin licensing regulation in vertebrates.

Keywords: DNA replication; cell cycle; checkpoint; genome stability; origin licensing; replication stress.

Figure 1.. Illustrations of normal and abnormal origin licensing outcomes.

A. Normal origin licensing and CDK2-dependent firing in G1 and S phase. B. Unscheduled licensing and firing leading to re-replication and genome instability. C. Underlicensing in G1 leading to replication stress and genome instability.

Figure 2.. Origin licensing.

The concerted action of ORC, CDC6, and CDT1 load hexamers of MCM onto DNA during G1 phase. A loaded MCM double hexamer constitutes a licensed origin; See also the text box.

Figure. 3.. Progression through G1 and S phase represented as a roller-coaster track.

Major decision points in G1 and at the G1/S transition are indicated in yellow, and a cell cycle checkpoint at or just prior to the G1/S transition is marked in green.