In search of the holy replicator

Abstract

After 40 years of searching for the eukaryotic replicator sequence, it is time to abandon the concept of 'the' replicator as a single genetic entity. Here I propose a 'relaxed replicon model' in which a positive initiator-replicator interaction is facilitated by a combination of several complex features of chromatin. An important question for the future is whether the positions of replication origins are simply a passive result of local chromatin structure or are actively localized to coordinate replication with other chromosomal activities.

Figure 1. The replicon model.

a | Original conception of the replicon model. “The replicon is assumed to be a circular structure carrying two specific genetic determinants. A structural gene (SG1) determines the synthesis of a diffusible active element, the initiator. The initiator acts on a replicator, allowing the beginning of the replication which proceeds along the circular structure”. Reproduced with permission from ref. 1 © (1964) Cold Spring Harbor Laboratory Press. b | The replicon model in the form that it was originally presumed to apply to eukaryotes.

Figure 2. Relaxed replicon model.

The hetero-hexameric origin-recognition complex (ORC) binds to naked DNA indiscriminately on its own, but the specificity of its binding to cellular chromatin in vivo is influenced by many factors. When presented with functionally inert (open or ‘indiscriminate’) chromatin (a), ORC binds nonspecifically. However, ORC might be directed to specific sites by (b) interacting proteins that chaperone ORC to specific sites or repress its binding to others–. Or (c), by superhelical tension, which can be created by nearby binding proteins (X) that might also position or remove nucleosomes, or otherwise create favourable ORC-binding sites. Superhelical tension can also be created by transcriptional activity, either upstream or downstream of gene promoters,. ORC can also be excluded from specific sites by (d) transcription, or by (e) general CpG DNA methylation, which can be quite prevalent. Additional features of chromatin that lie downstream of the initiator–replicator interaction also influence origin specification (BOX 2). This model necessarily invokes complexity — origin specification results from a different combination of targeting mechanisms for each chromosomal site, making it no longer useful to think of the replicator as a single common genetic entity.

Timeline. History of the hunt for the metazoan replicator

Timeline. History of the hunt for the metazoan replicator