Abstract

The entire process of duplication of the cell’s genetic material is started by the ATP -dependent Origin Recognition Complex (ORC) binding to chromosomes and then promoting the establishment of pre-Replicative Complexes (pre-RCs) at numerous sites within the genome. Following pre-RC assembly, multiple protein kinases and other regulatory processes control the recruitment of many replication proteins that initiate DNA synthesis. In the process the pre-RCs are destroyed. Stillman will discuss the biochemical steps in assembly of pre-RCs and present data on how the process of initiation of DNA replication is controlled by Cyclin-dependent protein kinases (CDKs), the Dbf4-Cdc7 protein kinase (DDK) and cell proliferation regulators such as the retinoblastoma protein Rb. Inherited genetic effects in genes encoding pre-RC proteins such as ORC cause Meier-Gorlin Syndrome, a disorder resulting in short stature and microcephaly. ORC mutations affect both DNA replication and centrosome duplication, contributing to the diverse phenotypes in such individuals.