Timing and spacing of ubiquitin-dependent DNA damage bypass

► Tolerance to replication-blocking DNA lesions is essential for genome stability. ► Damage bypass can be accomplished at replication forks or at daughter-strand gaps. ► A major part of damage bypass in eukaryotes is controlled by ubiquitylation of PCNA. ► Ubiquitin-dependent translesion synthesis occurs independently of replication forks. ► Higher eukaryotes also use fork-associated mechanisms for damage bypass. During its duplication, DNA, the carrier of our genetic information, is particularly vulnerable to decay, and the capacity of cells to deal with replication stress has been recognised as a major factor protecting us from genome instability and cancer. One of the major pathways controlling the bypass of DNA lesions during replication is activated by ubiquitylation of the sliding clamp, PCNA. Whereas monoubiquitylation of PCNA allows mutagenic translesion synthesis by damage-tolerant DNA polymerases, polyubiquitylation is required mainly for an error-free pathway that likely involves template switching. This review is focussed on our understanding of the timing of damage bypass during the cell cycle and the question of how it is coordinated with the progression of replication forks.