Just bypass it: mechanisms of DNA damage tolerance

Lesions on DNA threaten the integrity of replicating genomes, necessitating DNA damage tolerance mechanisms to bypass these lesions and ensure complete duplication of the genome. Lesion bypass by DNA polymerases can occur through either translesion DNA synthesis, which directly synthesizes across the damage, or template switching, which uses the undamaged sister strand as a template to circumvent the lesion. These processes are facilitated by replication fork reversal and/or replication repriming mechanisms, which modulate the progression of the replication fork and its positioning relative to the lesion. Despite the fundamental concepts of lesion bypass being accepted for decades, many aspects remain unresolved. This review revisits these concepts in light of recent advances and highlights the key questions persisting in the field.