Dynamics of DNA replication in a eukaryotic cell

Thomas Kelly, A. John Callegari

Research output: Contribution to journalArticlepeer-review

Abstract

Each genomic locus in a eukaryotic cell has a distinct average time of replication during S phase that depends on the spatial and temporal pattern of replication initiation events. Replication timing can affect genomic integrity because late replication is associated with an increased mutation rate. For most eukaryotes, the features of the genome that specify the location and timing of initiation events are unknown. To investigate these features for the fission yeast, Schizosaccharomyces pombe, we developed an integrative model to analyze large single-molecule and global genomic datasets. The model provides an accurate description of the complex dynamics of S. pombe DNA replication at high resolution. We present evidence that there are many more potential initiation sites in the S. pombe genome than previously identified and that the distribution of these sites is primarily determined by two factors: the sequence preferences of the origin recognition complex (ORC), and the interference of transcription with the assembly or stability of prereplication complexes (pre-RCs). We suggest that in addition to directly interfering with initiation, transcription has driven the evolution of the binding properties of ORC in S. pombe and other eukaryotic species to target pre-RC assembly to regions of the genome that are less likely to be transcribed.

Original languageEnglish (US)
Pages (from-to)4973-4982
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number11
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Keywords

  • DNA replication
  • Replication dynamics
  • Replication origins
  • Replication timing
  • Transcriptional interference

ASJC Scopus subject areas

  • General

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