Eukaryotic Replication Origins and Initiation of DNA Replication

Abstract

Eukaryotic deoxyribonucleic acid (DNA) replication begins at specific genomic sites called replication origins that serve as assembly sites for prereplication complexes (preRCs). PreRCs include proteins that recognise origin sequences, helicases that separate the two strands of DNA and accessory proteins that facilitate helicase binding and interaction with cell cycle regulatory pathways. Assembly of preRCs is required for initiation of DNA replication which occurs after those complexes recruit additional proteins including DNA polymerases . The sequence requirements for replication origins vary but they all include several distinct DNA elements that act synergistically to facilitate preRC assembly. The number of potential replication origins is higher than the number of actual replication initiation sites. Epigenetic processes and metabolic conditions dynamically select the location of replication initiation events of each cell cycle to insure complete and accurate replication of the entire genome in coordination with gene expression and chromatin condensation. Key Concepts: Replication initiates at distinct chromosomal locations that recruit prereplication (preRC) complexes. PreRCs are recruited sequentially, each step subject to strict regulation to prevent rereplication. Cyclin‐dependent kinases (CDK) levels change during the cell cycle. Low CDK activity is required for preRC assembly as cells exit mitosis. High CDK activity is required for activation of existing preRCs and initiation of DNA synthesis, while simultaneously suppressing assembly of new preRCs. Replication origin sequences vary among metazoans, but the functions of proteins that bind replication origins are conserved. Eukaryotic origins exhibit a modular structure. Modularity is detectable in single‐cell eukaryotes such as yeast and is more pronounced in metazoans, in which replication origins often cluster. Not all potential replication origins are activated in each cell cycle. Utilisation of replication origins is regulated dynamically to facilitate coordination with other metabolic processes occurring on chromatin. Either hyperactivation or suppression of replication origins can damage DNA and cause chromosomal rearrangements, suggesting that spacing replication initiation events at defined intervals facilitates genomic stability.