A new role for Holliday junction resolvase Yen1 in processing DNA replication intermediates exposes Dna2 as an accessory replicative helicase

DNA replication is mediated by a multi-protein complex known as the replisome. With the hexameric MCM (minichromosome maintenance) replicative helicase at its core, the replisome splits the parental DNA strands, forming replication forks (RFs), where it catalyses coupled leading and lagging strand DNA synthesis. While replication is a highly effective process, intrinsic and oncogene-induced replication stress impedes the progression of replisomes along chromosomes. As a consequence, RFs stall, arrest, and collapse, jeopardizing genome stability. In these instances, accessory fork progression and repair factors, orchestrated by the replication checkpoint, promote RF recovery, ensuring the chromosomes are fully replicated and can be safely segregated at cell division. Homologous recombination (HR) proteins play key roles in negotiating replication stress, binding at stalled RFs and shielding them from inappropriate processing. In addition, HR-mediated strand exchange reactions restart stalled or collapsed RFs and mediate error-free post-replicative repair. DNA transactions at stalled RFs further involve various DNA editing factors, notably helicases and nucleases. A study by Ölmezer et al. (2016) has recently identified a role for the structure-specific nuclease Yen1 (GEN1 in human) in the resolution of dead-end DNA replication intermediates after RF arrest. This new function of Yen1 is distinct from its previously known role as a Holliday junction resolvase, mediating the removal of branched HR intermediates, and it becomes essential for viable chromosome segregation in cells with a defective Dna2 helicase. These findings have revealed greater complexity in the tasks mediated by Yen1 and expose a replicative role for the elusive helicase activity of the conserved Dna2 nuclease-helicase.