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XLF and H2AX function in series to promote replication fork stability

XRCC4-like factor (XLF) is a non-homologous end joining (NHEJ) DNA double strand break repair protein. However, XLF deficiency leads to phenotypes in mice and humans that are not necessarily consistent with an isolated defect in NHEJ. Here we show that XLF functions during DNA replication. XLF under...

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Autores principales: Chen, Bo-Ruei, Quinet, Annabel, Byrum, Andrea K., Jackson, Jessica, Berti, Matteo, Thangavel, Saravanabhavan, Bredemeyer, Andrea L., Hindi, Issa, Mosammaparast, Nima, Tyler, Jessica K., Vindigni, Alessandro, Sleckman, Barry P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605786/
https://www.ncbi.nlm.nih.gov/pubmed/31123184
http://dx.doi.org/10.1083/jcb.201808134
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author Chen, Bo-Ruei
Quinet, Annabel
Byrum, Andrea K.
Jackson, Jessica
Berti, Matteo
Thangavel, Saravanabhavan
Bredemeyer, Andrea L.
Hindi, Issa
Mosammaparast, Nima
Tyler, Jessica K.
Vindigni, Alessandro
Sleckman, Barry P.
author_facet Chen, Bo-Ruei
Quinet, Annabel
Byrum, Andrea K.
Jackson, Jessica
Berti, Matteo
Thangavel, Saravanabhavan
Bredemeyer, Andrea L.
Hindi, Issa
Mosammaparast, Nima
Tyler, Jessica K.
Vindigni, Alessandro
Sleckman, Barry P.
author_sort Chen, Bo-Ruei
collection PubMed
description XRCC4-like factor (XLF) is a non-homologous end joining (NHEJ) DNA double strand break repair protein. However, XLF deficiency leads to phenotypes in mice and humans that are not necessarily consistent with an isolated defect in NHEJ. Here we show that XLF functions during DNA replication. XLF undergoes cell division cycle 7–dependent phosphorylation; associates with the replication factor C complex, a critical component of the replisome; and is found at replication forks. XLF deficiency leads to defects in replication fork progression and an increase in fork reversal. The additional loss of H2AX, which protects DNA ends from resection, leads to a requirement for ATR to prevent an MRE11-dependent loss of newly synthesized DNA and activation of DNA damage response. Moreover, H2ax(−/−):Xlf(−/−) cells exhibit a marked dependence on the ATR kinase for survival. We propose that XLF and H2AX function in series to prevent replication stress induced by the MRE11-dependent resection of regressed arms at reversed replication forks.
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spelling pubmed-66057862020-01-01 XLF and H2AX function in series to promote replication fork stability Chen, Bo-Ruei Quinet, Annabel Byrum, Andrea K. Jackson, Jessica Berti, Matteo Thangavel, Saravanabhavan Bredemeyer, Andrea L. Hindi, Issa Mosammaparast, Nima Tyler, Jessica K. Vindigni, Alessandro Sleckman, Barry P. J Cell Biol Research Articles XRCC4-like factor (XLF) is a non-homologous end joining (NHEJ) DNA double strand break repair protein. However, XLF deficiency leads to phenotypes in mice and humans that are not necessarily consistent with an isolated defect in NHEJ. Here we show that XLF functions during DNA replication. XLF undergoes cell division cycle 7–dependent phosphorylation; associates with the replication factor C complex, a critical component of the replisome; and is found at replication forks. XLF deficiency leads to defects in replication fork progression and an increase in fork reversal. The additional loss of H2AX, which protects DNA ends from resection, leads to a requirement for ATR to prevent an MRE11-dependent loss of newly synthesized DNA and activation of DNA damage response. Moreover, H2ax(−/−):Xlf(−/−) cells exhibit a marked dependence on the ATR kinase for survival. We propose that XLF and H2AX function in series to prevent replication stress induced by the MRE11-dependent resection of regressed arms at reversed replication forks. Rockefeller University Press 2019-07-01 2019-05-23 /pmc/articles/PMC6605786/ /pubmed/31123184 http://dx.doi.org/10.1083/jcb.201808134 Text en © 2019 Chen et al. http://www.rupress.org/terms/http://creativecommons.org/licenses/by-nc-sa/4.0/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 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Chen, Bo-Ruei
Quinet, Annabel
Byrum, Andrea K.
Jackson, Jessica
Berti, Matteo
Thangavel, Saravanabhavan
Bredemeyer, Andrea L.
Hindi, Issa
Mosammaparast, Nima
Tyler, Jessica K.
Vindigni, Alessandro
Sleckman, Barry P.
XLF and H2AX function in series to promote replication fork stability
title XLF and H2AX function in series to promote replication fork stability
title_full XLF and H2AX function in series to promote replication fork stability
title_fullStr XLF and H2AX function in series to promote replication fork stability
title_full_unstemmed XLF and H2AX function in series to promote replication fork stability
title_short XLF and H2AX function in series to promote replication fork stability
title_sort xlf and h2ax function in series to promote replication fork stability
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605786/
https://www.ncbi.nlm.nih.gov/pubmed/31123184
http://dx.doi.org/10.1083/jcb.201808134
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