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

Authors
  • 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
Type
Published Article
Journal
The Journal of Cell Biology
Publisher
The Rockefeller University Press
Publication Date
Mar 02, 2015
Volume
208
Issue
5
Pages
545–562
Identifiers
DOI: 10.1083/jcb.201406100
PMID: 25733713
Source
Medline
License
Unknown

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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