The replisome frequently encounters DNA damage, aberrant DNA structures, and transcription machinery that stall the replication fork through inhibition of replicative polymerases δ and ε [1]. In some cases involving damage to the leading strand template, fork stalling leads to uncoupling of DNA unwinding and synthesis, generating stretches of single-stranded (ss)DNA that are susceptible to nuclease cleavage and genetic rearrangements. Consequently, stalled forks threaten cell viability and genome stability. Several pathways function to maintain progression of the replication fork, either by removing or bypassing the fork-stalling lesion (Figure 1) [1, 2, 3]. These replication-repair and tolerance pathways are an integral part of genome duplication, and mutations in the proteins involved are associated with chromosome instability and human genetic syndromes including cancer. Translesion synthesis (TLS) involves direct bypass of the lesion in an error-prone manner by specialized DNA polymerases. Replication may also be continued by repriming synthesis past the lesion by PRIMPOL primase-polymerase or DNA polymerase α–primase. In contrast, fork remodeling pathways are a more elaborate means of damage tolerance through template switching—the use of the nascent strand on the sister chromatid as a template for error-free synthesis beyond the lesion. Template switching may occur either behind the fork or after fork reversal, a process involving generation of a Holliday junction from the reannealing of template strands and annealing of nascent strands (Figure 1) [4]. Reversed forks are intermediates in replication restart through fork restoration or recombination, and potentially facilitate excision repair of the fork-stalling lesion by placing it back in the context of double-stranded DNA.

This review focuses on recent structures of TLS polymerases and provides a survey of structural advances in fork remodeling and the initial stages of interstrand DNA crosslink (ICL) repair that take place at stalled replication forks. DNA primases involved in the repriming pathway are described in a separate review in this issue (Zabrady et al., unpublished).