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DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis
Human DNA polymerase η (Pol η) is best known for its role in responding to UV irradiation–induced genome damage. We have recently observed that Pol η is also required for the stability of common fragile sites (CFSs), whose rearrangements are considered a driving force of oncogenesis. Here, we explor...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639397/ https://www.ncbi.nlm.nih.gov/pubmed/23609533 http://dx.doi.org/10.1083/jcb.201207066 |
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author | Bergoglio, Valérie Boyer, Anne-Sophie Walsh, Erin Naim, Valeria Legube, Gaëlle Lee, Marietta Y.W.T. Rey, Laurie Rosselli, Filippo Cazaux, Christophe Eckert, Kristin A. Hoffmann, Jean-Sébastien |
author_facet | Bergoglio, Valérie Boyer, Anne-Sophie Walsh, Erin Naim, Valeria Legube, Gaëlle Lee, Marietta Y.W.T. Rey, Laurie Rosselli, Filippo Cazaux, Christophe Eckert, Kristin A. Hoffmann, Jean-Sébastien |
author_sort | Bergoglio, Valérie |
collection | PubMed |
description | Human DNA polymerase η (Pol η) is best known for its role in responding to UV irradiation–induced genome damage. We have recently observed that Pol η is also required for the stability of common fragile sites (CFSs), whose rearrangements are considered a driving force of oncogenesis. Here, we explored the molecular mechanisms underlying this newly identified role. We demonstrated that Pol η accumulated at CFSs upon partial replication stress and could efficiently replicate non-B DNA sequences within CFSs. Pol η deficiency led to persistence of checkpoint-blind under-replicated CFS regions in mitosis, detectable as FANCD2-associated chromosomal sites that were transmitted to daughter cells in 53BP1-shielded nuclear bodies. Expression of a catalytically inactive mutant of Pol η increased replication fork stalling and activated the replication checkpoint. These data are consistent with the requirement of Pol η–dependent DNA synthesis during S phase at replication forks stalled in CFS regions to suppress CFS instability by preventing checkpoint-blind under-replicated DNA in mitosis. |
format | Online Article Text |
id | pubmed-3639397 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-36393972013-10-29 DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis Bergoglio, Valérie Boyer, Anne-Sophie Walsh, Erin Naim, Valeria Legube, Gaëlle Lee, Marietta Y.W.T. Rey, Laurie Rosselli, Filippo Cazaux, Christophe Eckert, Kristin A. Hoffmann, Jean-Sébastien J Cell Biol Research Articles Human DNA polymerase η (Pol η) is best known for its role in responding to UV irradiation–induced genome damage. We have recently observed that Pol η is also required for the stability of common fragile sites (CFSs), whose rearrangements are considered a driving force of oncogenesis. Here, we explored the molecular mechanisms underlying this newly identified role. We demonstrated that Pol η accumulated at CFSs upon partial replication stress and could efficiently replicate non-B DNA sequences within CFSs. Pol η deficiency led to persistence of checkpoint-blind under-replicated CFS regions in mitosis, detectable as FANCD2-associated chromosomal sites that were transmitted to daughter cells in 53BP1-shielded nuclear bodies. Expression of a catalytically inactive mutant of Pol η increased replication fork stalling and activated the replication checkpoint. These data are consistent with the requirement of Pol η–dependent DNA synthesis during S phase at replication forks stalled in CFS regions to suppress CFS instability by preventing checkpoint-blind under-replicated DNA in mitosis. The Rockefeller University Press 2013-04-29 /pmc/articles/PMC3639397/ /pubmed/23609533 http://dx.doi.org/10.1083/jcb.201207066 Text en © 2013 Bergoglio 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 Bergoglio, Valérie Boyer, Anne-Sophie Walsh, Erin Naim, Valeria Legube, Gaëlle Lee, Marietta Y.W.T. Rey, Laurie Rosselli, Filippo Cazaux, Christophe Eckert, Kristin A. Hoffmann, Jean-Sébastien DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis |
title | DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis |
title_full | DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis |
title_fullStr | DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis |
title_full_unstemmed | DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis |
title_short | DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis |
title_sort | dna synthesis by pol η promotes fragile site stability by preventing under-replicated dna in mitosis |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639397/ https://www.ncbi.nlm.nih.gov/pubmed/23609533 http://dx.doi.org/10.1083/jcb.201207066 |
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