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FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress

Proper resolution of stalled replication forks is essential for genome stability. Purification of FBH1, a UvrD DNA helicase, identified a physical interaction with replication protein A (RPA), the major cellular single-stranded DNA (ssDNA)–binding protein complex. Compared with control cells, FBH1-d...

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Autores principales: Jeong, Yeon-Tae, Rossi, Mario, Cermak, Lukas, Saraf, Anita, Florens, Laurence, Washburn, Michael P., Sung, Patrick, Schildkraut, Carl, Pagano, Michele
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549964/
https://www.ncbi.nlm.nih.gov/pubmed/23319600
http://dx.doi.org/10.1083/jcb.201209002
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author Jeong, Yeon-Tae
Rossi, Mario
Cermak, Lukas
Saraf, Anita
Florens, Laurence
Washburn, Michael P.
Sung, Patrick
Schildkraut, Carl
Pagano, Michele
author_facet Jeong, Yeon-Tae
Rossi, Mario
Cermak, Lukas
Saraf, Anita
Florens, Laurence
Washburn, Michael P.
Sung, Patrick
Schildkraut, Carl
Pagano, Michele
author_sort Jeong, Yeon-Tae
collection PubMed
description Proper resolution of stalled replication forks is essential for genome stability. Purification of FBH1, a UvrD DNA helicase, identified a physical interaction with replication protein A (RPA), the major cellular single-stranded DNA (ssDNA)–binding protein complex. Compared with control cells, FBH1-depleted cells responded to replication stress with considerably fewer double-strand breaks (DSBs), a dramatic reduction in the activation of ATM and DNA-PK and phosphorylation of RPA2 and p53, and a significantly increased rate of survival. A minor decrease in ssDNA levels was also observed. All these phenotypes were rescued by wild-type FBH1, but not a FBH1 mutant lacking helicase activity. FBH1 depletion had no effect on other forms of genotoxic stress in which DSBs form by means that do not require ssDNA intermediates. In response to catastrophic genotoxic stress, apoptosis prevents the persistence and propagation of DNA lesions. Our findings show that FBH1 helicase activity is required for the efficient induction of DSBs and apoptosis specifically in response to DNA replication stress.
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spelling pubmed-35499642013-07-21 FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress Jeong, Yeon-Tae Rossi, Mario Cermak, Lukas Saraf, Anita Florens, Laurence Washburn, Michael P. Sung, Patrick Schildkraut, Carl Pagano, Michele J Cell Biol Research Articles Proper resolution of stalled replication forks is essential for genome stability. Purification of FBH1, a UvrD DNA helicase, identified a physical interaction with replication protein A (RPA), the major cellular single-stranded DNA (ssDNA)–binding protein complex. Compared with control cells, FBH1-depleted cells responded to replication stress with considerably fewer double-strand breaks (DSBs), a dramatic reduction in the activation of ATM and DNA-PK and phosphorylation of RPA2 and p53, and a significantly increased rate of survival. A minor decrease in ssDNA levels was also observed. All these phenotypes were rescued by wild-type FBH1, but not a FBH1 mutant lacking helicase activity. FBH1 depletion had no effect on other forms of genotoxic stress in which DSBs form by means that do not require ssDNA intermediates. In response to catastrophic genotoxic stress, apoptosis prevents the persistence and propagation of DNA lesions. Our findings show that FBH1 helicase activity is required for the efficient induction of DSBs and apoptosis specifically in response to DNA replication stress. The Rockefeller University Press 2013-01-21 /pmc/articles/PMC3549964/ /pubmed/23319600 http://dx.doi.org/10.1083/jcb.201209002 Text en © 2013 Jeong 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
Jeong, Yeon-Tae
Rossi, Mario
Cermak, Lukas
Saraf, Anita
Florens, Laurence
Washburn, Michael P.
Sung, Patrick
Schildkraut, Carl
Pagano, Michele
FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress
title FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress
title_full FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress
title_fullStr FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress
title_full_unstemmed FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress
title_short FBH1 promotes DNA double-strand breakage and apoptosis in response to DNA replication stress
title_sort fbh1 promotes dna double-strand breakage and apoptosis in response to dna replication stress
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549964/
https://www.ncbi.nlm.nih.gov/pubmed/23319600
http://dx.doi.org/10.1083/jcb.201209002
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