Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347643/
https://www.ncbi.nlm.nih.gov/pubmed/25733713
http://dx.doi.org/10.1083/jcb.201406100
_version_ 1782359853588545536
author 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
author_facet 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
author_sort Thangavel, Saravanabhavan
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4347643
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-43476432015-09-02 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 J Cell Biol Research Articles 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. The Rockefeller University Press 2015-03-02 /pmc/articles/PMC4347643/ /pubmed/25733713 http://dx.doi.org/10.1083/jcb.201406100 Text en © 2015 Thangavel et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
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
DNA2 drives processing and restart of reversed replication forks in human cells
title DNA2 drives processing and restart of reversed replication forks in human cells
title_full DNA2 drives processing and restart of reversed replication forks in human cells
title_fullStr DNA2 drives processing and restart of reversed replication forks in human cells
title_full_unstemmed DNA2 drives processing and restart of reversed replication forks in human cells
title_short DNA2 drives processing and restart of reversed replication forks in human cells
title_sort dna2 drives processing and restart of reversed replication forks in human cells
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347643/
https://www.ncbi.nlm.nih.gov/pubmed/25733713
http://dx.doi.org/10.1083/jcb.201406100
work_keys_str_mv AT thangavelsaravanabhavan dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT bertimatteo dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT levikovamaryna dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT pintocosimo dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT gomathinayagamshivasankari dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT vujanovicmarko dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT zellwegerralph dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT moorehayley dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT leeeuhan dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT hendricksonerica dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT cejkapetr dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT stewartsheila dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT lopesmassimo dna2drivesprocessingandrestartofreversedreplicationforksinhumancells
AT vindignialessandro dna2drivesprocessingandrestartofreversedreplicationforksinhumancells