The Silencing Face of DNA Replication: Gene Repression Mediated by DNA Replication Factors

DNA replication in eukaryotes initiates at multiple origins. The activation of these origins is a critically important event in the life of each cell and is tightly regulated by numerous highly conserved trans-factors. Saccharomyces cerevisiae origins (called Autonomously Replicating Sequences, ARSs) contain a core A element called ACS (ARS Consensus Sequence), plus an array of auxiliary B elements. Most ARSs fire at their chromosomal positions, but there are numerous dormant ARSs as well. Instead of being origins, these dormant ARSs serve as silencer elements, which function in the epigenetic repression of nearby genes. Even more, many DNA replication trans-factors have also been reported to affect gene silencing. This puzzling functional duality of ARS and DNA replication factors has attracted significant interest. Evidence from other species has suggested that the overlap between gene silencing and DNA replication operates in other eukaryotes. In this chapter we will review in detail the activity of ARSs as origins of replication and as silencers. We will focus on sequence dissimilarities between silencer and origin ARSs and will propose a model for the functional duality of DNA replication factors.