Eukaryotic DNA replication origins: many choices for appropriate answers

Abstract

At each cell division in humans, DNA replication starts from 50,000 DNA replication origins, which are at specific locations along the chromosomes and from which DNA synthesis proceeds bidirectionally. In contrast to origins in bacteria or Saccharomyces cerevisiae, a specific consensus sequence has not yet been identified in metazoans and their selection mechanism seems to be mainly epigenetic. DNA replication origins have a common 12 bp consensus sequence in S. cerevisiae but only a few of them are used in vivo. In Schizosaccharomyces pombe, DNA replication origins are characterized by AT-rich islands. In metazoans, both CpG islands and AT-rich stretches may characterize the origins. Replication origins are in excess relative to their use in each cell cycle. They fall into three main classes: used all the time (constitutive), used in an apparently stochastic manner in each cell cycle (flexible; most origins are of this type) and used in specific growth or differentiation conditions (dormant). Replication stress and checkpoint controls can regulate the use of flexible origins and the activation of dormant origins and can repress late replication origins. Transcriptional features and development also modulate the use and position of the replication origins along the genome. Chromosome structure and chromatin organization have a big impact on origin selection and function. Replication origins are organized in clusters of consecutive origins that are synchronously activated.