Disease-associated DNA2 nuclease–helicase protects cells from lethal chromosome under-replication

Falquet, Benoît, Ölmezer, Gizem, Enkner, Franz, Klein, Dominique, Challa, Kiran, Appanah, Rowin, Gasser, Susan M and Rass, Ulrich (2020) Disease-associated DNA2 nuclease–helicase protects cells from lethal chromosome under-replication. Nucleic Acids Research, 48 (13). pp. 7265-7278. ISSN 1362-4962

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DNA2 is an essential nuclease–helicase implicated in DNA repair, lagging-strand DNA synthesis, and the recovery of stalled DNA replication forks (RFs). In Saccharomyces cerevisiae, dna2Δ inviability is reversed by deletion of the conserved helicase PIF1 and/or DNA damage checkpoint-mediator RAD9. It has been suggested that Pif1 drives the formation of long 5′-flaps during Okazaki fragment maturation, and that the essential function of Dna2 is to remove these intermediates. In the absence of Dna2, 5′-flaps are thought to accumulate on the lagging strand, resulting in DNA damage-checkpoint arrest and cell death. In line with Dna2’s role in RF recovery, we find that the loss of Dna2 results in severe chromosome under-replication downstream of endogenous and exogenous RF-stalling. Importantly, unfaithful chromosome replication in Dna2-mutant cells is exacerbated by Pif1, which triggers the DNA damage checkpoint along a pathway involving Pif1’s ability to promote homologous recombination-coupled replication. We propose that Dna2 fulfils its essential function by promoting RF recovery, facilitating replication completion while suppressing excessive RF restart by recombination-dependent replication (RDR) and checkpoint activation. The critical nature of Dna2’s role in controlling the fate of stalled RFs provides a framework to rationalize the involvement of DNA2 in Seckel syndrome and cancer.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Subjects: Q Science > Q Science (General) > Q0179.9 Research
Q Science > Q Science (General)
Depositing User: Paula Amiet-West
Date Deposited: 22 Jun 2020 06:43
Last Modified: 16 Mar 2022 12:30
URI: http://sro.sussex.ac.uk/id/eprint/91997

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UnsetUnsetSwiss National Science Foundation31003A_176286