First-passage problems in DNA replication: effects of template tension on stepping and exonuclease activities of a DNA polymerase motor

Abstract

A DNA polymerase (DNAP) replicates a template DNA strand. It also exploits the template as the track for its own motor-like mechanical movement. In the polymerase mode it elongates the nascent DNA by one nucleotide in each step. But, whenever it commits an error by misincorporating an incorrect nucleotide, it can switch to an exonuclease mode. In the latter mode it excises the wrong nucleotide before switching back to its polymerase mode. We develop a stochastic kinetic model of DNA replication that mimics an {\it in-vitro} experiment where a single-stranded DNA, subjected to a mechanical tension $F$, is converted to a double-stranded DNA by a single DNAP. The $F$-dependence of the average rate of replication, which depends on the rates of both polymerase and exonuclease activities of the DNAP, is in good qualitative agreement with the corresponding experimental results. We introduce 9 novel distinct {\it conditional dwell times} of a DNAP. Using the methods of first-passage times, we also derive the exact analytical expressions for the probability distributions of these conditional dwell times. The predicted $F$-dependence of these distributions are, in principle, accessible to single-molecule experiments.