An updated view on lagging strand DNA replication: implications for the replication stress response

Abstract

The process of DNA replication is inherently asymmetric. While the leading strand is synthesized continuously, the lagging strand is copied in small fragments, the Okazaki fragments, requiring the repeated priming by the DNA polymerase alpha/Primase complex (Pol α/Pri). Current evidence is consistent with a semi-distributive model for priming in the lagging strand, as Pol α/Pri acts associated to the replisome and also as a free complex. In addition, there is a strong link between the dynamics of replication in the lagging strand and the basal activation of the replication stress response (RSR) during an unperturbed S phase. We hypothesize that the RSR monitors the generation of Okazaki fragments to control the synthesis of DNA in what we call the DNA replication control (DRC) mode of the RSR. The DRC enforces a gradual progression of DNA replication by restricting origin firing, what is necessary to establish the replication program in the cell and to prevent the appearance of genomic instability. Thus, the RSR coordinates the replication program in the cell, modulating the progression of DNA replication to prevent the exhaustion of cellular resources that would endanger the stability of the genome.