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DNA2 drives processing and restart of reversed replication forks in human cells


Thangavel, Saravanabhavan; Berti, Matteo; Levikova, Maryna; Pinto, Cosimo; Gomathinayagam, Shivasankari; Vujanovic, Marko; Zellweger, Ralph; Moore, Hayley; Lee, Eu Han; Hendrickson, Eric A; Cejka, Petr; Stewart, Sheila; Lopes, Massimo; Vindigni, Alessandro (2015). DNA2 drives processing and restart of reversed replication forks in human cells. Journal of Cell Biology, 208(5):545-562.

Abstract

Accurate processing of stalled or damaged DNA replication forks is paramount to genomic integrity and recent work points to replication fork reversal and restart as a central mechanism to ensuring high-fidelity DNA replication. Here, we identify a novel DNA2- and WRN-dependent mechanism of reversed replication fork processing and restart after prolonged genotoxic stress. The human DNA2 nuclease and WRN ATPase activities functionally interact to degrade reversed replication forks with a 5'-to-3' polarity and promote replication restart, thus preventing aberrant processing of unresolved replication intermediates. Unexpectedly, EXO1, MRE11, and CtIP are not involved in the same mechanism of reversed fork processing, whereas human RECQ1 limits DNA2 activity by preventing extensive nascent strand degradation. RAD51 depletion antagonizes this mechanism, presumably by preventing reversed fork formation. These studies define a new mechanism for maintaining genome integrity tightly controlled by specific nucleolytic activities and central homologous recombination factors.

Abstract

Accurate processing of stalled or damaged DNA replication forks is paramount to genomic integrity and recent work points to replication fork reversal and restart as a central mechanism to ensuring high-fidelity DNA replication. Here, we identify a novel DNA2- and WRN-dependent mechanism of reversed replication fork processing and restart after prolonged genotoxic stress. The human DNA2 nuclease and WRN ATPase activities functionally interact to degrade reversed replication forks with a 5'-to-3' polarity and promote replication restart, thus preventing aberrant processing of unresolved replication intermediates. Unexpectedly, EXO1, MRE11, and CtIP are not involved in the same mechanism of reversed fork processing, whereas human RECQ1 limits DNA2 activity by preventing extensive nascent strand degradation. RAD51 depletion antagonizes this mechanism, presumably by preventing reversed fork formation. These studies define a new mechanism for maintaining genome integrity tightly controlled by specific nucleolytic activities and central homologous recombination factors.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2 March 2015
Deposited On:19 Mar 2015 08:40
Last Modified:08 Dec 2017 12:34
Publisher:Rockefeller University Press
ISSN:0021-9525
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1083/jcb.201406100
PubMed ID:25733713

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