Discontinuous leading-strand synthesis: a stop–start story

Reconstitution experiments using replication proteins from a number of different model organisms have firmly established that, in vitro, DNA replication is semi-discontinuous: continuous on the leading strand and discontinuous on the lagging strand. The mechanism by which DNA is replicated in vivo is less clear. In fact, there have been many observations of discontinuous replication in the absence of exogenous DNA-damaging agents. It has also been proposed that replication is discontinuous on the leading strand at least in part because of DNA lesion bypass. Several recent studies have revealed mechanistic details of pathways where replication of the leading strand introduces discontinuities. These mechanisms and their potential contributions to observations of discontinuous replication in vivo will be discussed.