Chromatin determinants of origin selection and activation

DNA replication is an essential cell cycle-regulated process necessary for the accurate duplication of the genome. DNA replication begins at cis-acting replicator loci (replication origins) that are distributed throughout each of the eukaryotic chromosomes. The first factor to bind to the replicator is the origin recognition complex (ORC). ORC directs the recruitment of the Mcm2-7 helicase complex to form the pre-replication complex (pre-RC), licensing the origin for activation. Origin selection and activation are dependent on both DNA sequence and epigenetic features. The cis-acting sequence elements that function as replicators are well defined in Saccharomyces cerevisiae; in contrast, metazoan replicators are not defined by primary sequence, but rather by secondary structural features like G-quadruplexes. In both yeast and higher eukaryotes, however, cis-acting sequences or G-quadruplexes are not sufficient for origin function, implying the necessity for epigenetic mechanisms in regulating the selection and activation of DNA replication origins. In higher eukaryotes, the chromatin landscape surrounding origins of replication is important for the plasticity of the DNA replication program, allowing it to adapt and respond to developmental and environmental signals. Here we describe the role of chromatin structure and histone modifications in specifying and regulating eukaryotic DNA replication origins.

Duke Scholars

Author David MacAlpine Pharmacology & Cancer Biology