Role of Small-Molecule Modifiers in Replication Initiation

Posttranslational modification of proteins through attachment of ubiquitin or ubiquitin-like proteins (UBLs) changes the three-dimensional structure of the modified factors and affects their activity, interactions, and turnover. Ubiquitin and UBLs constitute a very versatile and flexible system of protein modification and regulate almost every aspect of cell biology. In this chapter we focus on the role of these small protein modifiers in regulation of DNA replication initiation. We review the accumulated knowledge showing how ubiquitin-driven proteasomal degradation leads to creation of sequential, non-overlapping stages of the cell cycle allowing DNA replication initiation and how it prevents re-replication during S phase. We also explain the role ubiquitylation plays in the inhibition of DNA replication initiation in response to DNA damage. As the regulation of replication factors is often executed through modifications with both small protein modifiers and phosphorylation we also discuss the important crossovers between these two regulatory mechanisms. Finally, we review our present knowledge of regulation of DNA replication initiation by non-degradative forms of ubiquitylation and modifications with Nedd8 and SUMO.