Genomic approaches to the initiation of DNA replication and chromatin structure reveal a complex relationship

Abstract

The mechanisms regulating the coordinate activation of tens of thousands of replication origins in multicellular organisms remain poorly explored. Recent advances in genomics have provided valuable information about the sites at which DNA replication is initiated and the selection mechanisms of specific sites in both yeast and vertebrates. Studies in yeast have advanced to the point that it is now possible to develop convincing models for origin selection. A general model has emerged, but yeast data have also revealed an unsuspected diversity of strategies for origin positioning. We focus here on the ways in which chromatin structure may affect the formation of pre-replication complexes, a prerequisite for origin activation. We also discuss the need to exercise caution when trying to extrapolate yeast models directly to more complex vertebrate genomes.

Figure 1:

Multifactorial regulation of origin specification. (A) In S. cerevisiae, two classes of origin have been described, according to sensitivity to the BAH domain of the Orc1 subunit. All origins possess a conserved motif, ACS, which is bound by the ORC complex, and this ACS motif specifies a low level of nucleosome occupancy, creating a permissive environment for ORC binding. At orc1-bahΔ-sensitive origins, the Orc1-BAH domain interacts directly or indirectly with the nucleosome in position −1, affecting its positioning, thereby reducing the size of the NFR (This figure is adapted from [24]). (B) Regulation of metazoan origins is less well understood, but several factors have been identified as probably or possibly involved in regulating origin specification. In cis, a replication origin may be determined by several elements, such as CGI, NFRs or TF binding sites. These elements are often co-localized or influence each other, blurring identification of the determinant feature for origin specification. For replication initiation, the Pre-RC complex must be recruited to the origin, but the exact mechanism underlying this recruitment remains unclear. It has been suggested that the binding of a combination of TFs might lead to chromatin being organized into a structure permissive for Pre-RC recruitment. Direct or indirect contacts between TFs and Pre-RC subunits may also contribute to origin selection.