Balancing eukaryotic replication asymmetry with replication fidelity

Abstract

Coordinated replication of eukaryotic nuclear genomes is asymmetric, with copying of a leading strand template preceding discontinuous copying of the lagging strand template. Replication is catalyzed by DNA polymerases α, δ and ɛ, enzymes that are related yet differ in physical and biochemical properties, including fidelity. Recent studies suggest that Pol ɛ is normally the primary leading strand replicase, whereas most synthesis by Pol δ occurs during lagging strand replication. New studies show that replication asymmetry can generate strand-specific genome instability resulting from biased deoxynucleotide pools and unrepaired ribonucleotides incorporated into DNA during replication, and that the eukaryotic replication machinery has evolved to most efficiently correct those replication errors that are made at the highest rates.

Figure 1. Assigning yeast Pol δ and Pol ε to specific strands

(A) Biased error rates in vitro and biased, orientation-specific mutation rates in vivo for two variant yeast replicases. See text for description. Adapted from [9] with permission. (B) Whole genome analysis of the distribution of transition substitutions relative to origins of replication in a pol3-L612M msh2Δ yeast strain. See text for description. Adapted from [17] with permission. (C) Model for division of polymerase labor at the eukaryotic replication fork.

Figure 2. Strand-specific genome instability due to replication asymmetry

(A) Strand-specific distribution of mutational hotspots in yeast strains with rnr1 mutations that differentially affect dNTP pools and checkpoint activation. See text for description. Adapted from [26] with permission. (B) Orientation-dependent CA dinucleotide deletion rates in pol2-M644G rnh201 yeast strains [30]. See text for description.

Figure 3. Reciprocal relationship between generating and correcting replication errors

(A) Preferential MMR of replication errors generated by Pol α. See text for description. (B) Ideas for reciprocity between generating and correcting errors made by Pols α and δ during lagging strand replication. See text for description. Adapted from [39] with permission.