Regulation of timing of replication

Introduction to DNA replication DNA replication is a process fundamental to cell proliferation. Eukaryotic cells must replicate their DNA once and only once per cell cycle. In addition, after each DNA replication, the epigenetic information, such as DNA methylation and histone modifications, that constitute the memory and the identity of the cells must also be replicated. These functional constraints might have caused eukaryotes to evolve complex tissue specific replication programs, perhaps because the timing during S phase at which each DNA segment replicates is critical for the transmission of epigenetic memory. DNA replication begins by the recruitment of the replication machinery at specific sites in the genome called “origins.” DNA replicated from a single origin is referred to as a replicon. DNA synthesis in each replicon is initiated at an origin and proceeds bidirectionally. These replicons eventually fuse resulting in complete genomic duplication. Initiation of DNA replication involves the following steps. Origin recognition The origin recognition complex (ORC) was originally identified in budding yeast and is evolutionally conserved across species (Bell and Stillman, 1992). It is composed of six subunits (ORC1 to ORC6) that act as initiators and bind to the origin sites in eukaryotic DNA. Mammalian ORC consists of a stable core complex of subunits ORC 2, 3, 4, and 5 which interact feebly with ORC1 and ORC6.