S Phase Duration Is Determined by Local Rate and Global Organization of Replication

SIMPLE SUMMARY: In order for a cell to divide into two cells, it must first copy its DNA. Although the time required for this process tends not to vary much, many examples of the importance of variability have been reported. In this review, we discuss the methods used to study this question, present some of the examples of variation, and attempt to explain the factors that determine the time required in simple terms. We will show that the overall time depends on the rate of DNA replication within a region, and on the temporal organization of the regions relative to each other. ABSTRACT: The duration of the cell cycle has been extensively studied and a wide degree of variability exists between cells, tissues and organisms. However, the duration of S phase has often been neglected, due to the false assumption that S phase duration is relatively constant. In this paper, we describe the methodologies to measure S phase duration, summarize the existing knowledge about its variability and discuss the key factors that control it. The local rate of replication (LRR), which is a combination of fork rate (FR) and inter-origin distance (IOD), has a limited influence on S phase duration, partially due to the compensation between FR and IOD. On the other hand, the organization of the replication program, specifically the amount of replication domains that fire simultaneously and the degree of overlap between the firing of distinct replication timing domains, is the main determinant of S phase duration. We use these principles to explain the variation in S phase length in different tissues and conditions.