Unwinding or cutting ties for good: helicases and nucleases at stalled replication forks

DNA replication is one of the most central processes of life. This task is performed by replicative machineries, which have to travel the entire length of each chromosome to ensure genome duplication. However, replication might stall due to natural impediments or external stress factors. The cells, then, rely on multiple accessory helicases and nucleases to unwind or cut the DNA in order to resume DNA synthesis and allow chromosome segregation at mitosis. Despite the importance of these factors, our understanding of their exact role remains incomplete.
In this work, we used budding yeast as a model organism to understand the role of the conserved nuclease-helicase Dna2 in replication. Taking advantage of its genetic interaction with Yen1, we first uncovered the role of the Dna2 helicase activity in the replication stress response and uncovered a non-canonical role of Yen1 in resolving DNA replication intermediates. We, then, extended our understanding and found that both the helicase and nuclease activities of Dna2 ensure an essential function in attending stalled replication forks to promote full genome duplication. These results offer new insights in the replication stress response and provide a new framework to understand the human pathologies associated with DNA2.