Replication origins in metazoan chromosomes: fact or fiction?

Abstract

The process by which eukaryotic cells decide when and where to initiate DNA replication has been illuminated in yeast, where specific DNA sequences (replication origins) bind a unique group of proteins (origin recognition complex) next to an easily unwound DNA sequence at which replication can begin. The origin recognition complex provides a platform on which additional proteins assemble to form a pre-replication complex that can be activated at S-phase by specific protein kinases. Remarkably, multicellular eukaryotes, such as frogs, flies, and mammals (metazoa), have counterparts to these yeast proteins that are required for DNA replication. Therefore, one might expect metazoan chromosomes to contain specific replication origins as well, a hypothesis that has long been controversial. In fact, recent results strongly support the view that DNA replication origins in metazoan chromosomes consist of one or more high frequency initiation sites and perhaps several low frequency ones that together can appear as a nonspecific initiation zone. Specific replication origins are established during G1-phase of each cell cycle by multiple parameters that include nuclear structure, chromatin structure, DNA sequence, and perhaps DNA modification. Such complexity endows metazoa with the flexibility to change both the number and locations of replication origins in response to the demands of animal development.

Xenopus origin recognition complex (ORC) initiates DNA replication preferentially at sequences targeted by Schizosaccharomyces pombe ORC

“…The fact that nature has uniquely designed the SpOrc4 protein to target specific asymmetric AT‐rich sequences suggests that the same or similar sequences constitute an essential component of many, if not all, eukaryotic replication origins. We suggest that most, perhaps all, ORCs preferentially target asymmetric A:T‐rich sequences, but that the actual binding may be affected by epigenetic parameters (DePamphilis, 1999). Therefore, the extent of origin specificity will vary with animal development and cell differentiation.…”

“…DNA replication begins when a six subunit complex called the ‘origin recognition complex’ (ORC) binds to DNA and initiates assembly of a pre‐replication complex (pre‐RC) consisting of proteins including ORC, Cdc6(Cdc18), Cdt1 and Mcm 2–7 (Bell and Dutta, 2002). Site‐specific initiation of DNA replication has not been detected in frog eggs or egg extracts (Hyrien et al ., 1995; Blow et al ., 2001), but in yeast, flies and mammals, DNA replication generally begins at specific genomic sites (replication origins) that are determined by cis ‐acting sequences (DePamphilis, 1999; Altman and Fanning, 2001; Bell and Dutta, 2002; Kong and DePamphilis, 2002; and references therein). However, efforts to elucidate the mechanism of site selection using purified ORCs have met with limited success.…”

The BAH domain facilitates the ability of human Orc1 protein to activate replication origins in vivo

“…Developmental changes in origin density also occur during specific stages in mammalian development (Norio et al , 2005). Thus, metazoan genomes contain many potential initiation sites for DNA replication, but during development, some of these sites are selectively activated while others are suppressed (‘Jesuit Model’; DePamphilis, 1999).…”

Replication timing and cell differentiation

“…Condensation prevents replicon initiations, while unfolding favors formation of replicon origins. While unfolding of chromatin may be the initial step of replicon initiation (Lawlis et al, 1996), a number of other proteins then become involved (DePamphilis, 1999). In the present paper, two specific proteins that have a negative or positive influence upon the initial phase of replicon initiation will be considered.…”