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

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...

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Veröffentlicht in:The Journal of cell biology Jg. 208; H. 5; S. 545
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 02.03.2015
Schlagworte:
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell Line
DNA Helicases - genetics
DNA Helicases - metabolism
DNA Repair Enzymes - genetics
DNA Repair Enzymes - metabolism
DNA Replication - physiology
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Exodeoxyribonucleases - genetics
Exodeoxyribonucleases - metabolism
Humans
MRE11 Homologue Protein
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Rad51 Recombinase - genetics
Rad51 Recombinase - metabolism
RecQ Helicases - genetics
RecQ Helicases - metabolism
Werner Syndrome Helicase
ISSN:1540-8140, 1540-8140
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
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ISSN:1540-8140
1540-8140
DOI:10.1083/jcb.201406100