Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
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
_version_ 1782475952923607040
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
work_keys_str_mv AT bergogliovalerie dnasynthesisbypolēpromotesfragilesitestabilitybypreventingunderreplicateddnainmitosis
AT boyerannesophie dnasynthesisbypolēpromotesfragilesitestabilitybypreventingunderreplicateddnainmitosis
AT walsherin dnasynthesisbypolēpromotesfragilesitestabilitybypreventingunderreplicateddnainmitosis
AT naimvaleria dnasynthesisbypolēpromotesfragilesitestabilitybypreventingunderreplicateddnainmitosis
AT legubegaelle dnasynthesisbypolēpromotesfragilesitestabilitybypreventingunderreplicateddnainmitosis
AT leemariettaywt dnasynthesisbypolēpromotesfragilesitestabilitybypreventingunderreplicateddnainmitosis
AT reylaurie dnasynthesisbypolēpromotesfragilesitestabilitybypreventingunderreplicateddnainmitosis
AT rossellifilippo dnasynthesisbypolēpromotesfragilesitestabilitybypreventingunderreplicateddnainmitosis
AT cazauxchristophe dnasynthesisbypolēpromotesfragilesitestabilitybypreventingunderreplicateddnainmitosis
AT eckertkristina dnasynthesisbypolēpromotesfragilesitestabilitybypreventingunderreplicateddnainmitosis
AT hoffmannjeansebastien dnasynthesisbypolēpromotesfragilesitestabilitybypreventingunderreplicateddnainmitosis