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In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Cells have evolved mechanisms to protect, restart and repair perturbed replication forks, allowing full genome duplication, even under replication stress. Interrogating the interplay between nuclease-helicase Dna2 and Holliday junction HJ resolvase Yen1, we find the Dna2 helicase activity acts parallel to homologous recombination HR in promoting DNA replication and chromosome detachment at mitosis after replication fork stalling.
Yen1, but not the HJ resolvases Slx1-Slx4 and MusMms4, safeguards chromosome segregation by removing replication intermediates that escape Dna2. These findings explain the exquisite replication stress sensitivity of Dna2 helicase-defective cells, and identify a non-canonical role for Yen1 in the processing of replication intermediates that is distinct from HJ resolution.
The involvement of Dna2 helicase activity in completing replication may have implications for DNA2 -associated pathologies, including cancer and Seckel syndrome. Duplication of the genome requires the passage of DNA replication forks along the entire length of every chromosome. If segments of DNA remain unreplicated, physical links between the nascent sister chromatids persist, which can lead to aberrant chromosome segregation 1. Replication fork collapse, characterized by replisome inactivation and DNA breakage, induces recombinogenic DNA lesions and gross chromosomal instability 2.
Consistently, replication stress, which increases the risk of replication fork stalling, arrest, and collapse, has been recognized as a driver in cancerogenesis 3.
