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The hereditary N363K POLE exonuclease mutant extends PPAP tumor spectrum to glioblastomas by causing DNA damage and aneuploidy in addition to increased mismatch mutagenicity

The exonuclease domain of DNA polymerases epsilon's catalytic subunit (POLE) removes misincorporated nucleotides, called proofreading. POLE-exonuclease mutations cause colorectal- and endometrial cancers with an extreme burden of single nucleotide substitutions. We recently reported that partic...

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Autores principales: Labrousse, Guillaume, Vande Perre, Pierre, Parra, Genis, Jaffrelot, Marion, Leroy, Laura, Chibon, Frederic, Escudie, Frederic, Selves, Janick, Hoffmann, Jean-Sebastien, Guimbaud, Rosine, Lutzmann, Malik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006997/
https://www.ncbi.nlm.nih.gov/pubmed/36915289
http://dx.doi.org/10.1093/narcan/zcad011
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author Labrousse, Guillaume
Vande Perre, Pierre
Parra, Genis
Jaffrelot, Marion
Leroy, Laura
Chibon, Frederic
Escudie, Frederic
Selves, Janick
Hoffmann, Jean-Sebastien
Guimbaud, Rosine
Lutzmann, Malik
author_facet Labrousse, Guillaume
Vande Perre, Pierre
Parra, Genis
Jaffrelot, Marion
Leroy, Laura
Chibon, Frederic
Escudie, Frederic
Selves, Janick
Hoffmann, Jean-Sebastien
Guimbaud, Rosine
Lutzmann, Malik
author_sort Labrousse, Guillaume
collection PubMed
description The exonuclease domain of DNA polymerases epsilon's catalytic subunit (POLE) removes misincorporated nucleotides, called proofreading. POLE-exonuclease mutations cause colorectal- and endometrial cancers with an extreme burden of single nucleotide substitutions. We recently reported that particularly the hereditary POLE exonuclease mutation N363K predisposes in addition to aggressive giant cell glioblastomas. We knocked-in this mutation homozygously into human cell lines and compared its properties to knock-ins of the likewise hereditary POLE L424V mutation and to a complete proofreading-inactivating mutation (exo-null). We found that N363K cells have higher mutation rates as both L424V- or exo-null mutant cells. In contrast to L424V cells, N363K cells expose a growth defect, replication stress and DNA damage. In non-transformed cells, these burdens lead to aneuploidy but macroscopically normal nuclei. In contrast, transformed N363K cells phenocopy the enlarged and disorganized nuclei of giant cell glioblastomas. Taken together, our data characterize a POLE exonuclease domain mutant that not only causes single nucleotide hypermutation, but in addition DNA damage and chromosome instability, leading to an extended tumor spectrum. Our results expand the understanding of the polymerase exonuclease domain and suggest that an assessment of both the mutational potential and the genetic instability might refine classification and treatment of POLE-mutated tumors.
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spelling pubmed-100069972023-03-12 The hereditary N363K POLE exonuclease mutant extends PPAP tumor spectrum to glioblastomas by causing DNA damage and aneuploidy in addition to increased mismatch mutagenicity Labrousse, Guillaume Vande Perre, Pierre Parra, Genis Jaffrelot, Marion Leroy, Laura Chibon, Frederic Escudie, Frederic Selves, Janick Hoffmann, Jean-Sebastien Guimbaud, Rosine Lutzmann, Malik NAR Cancer DNA Damage Sensing and Repair The exonuclease domain of DNA polymerases epsilon's catalytic subunit (POLE) removes misincorporated nucleotides, called proofreading. POLE-exonuclease mutations cause colorectal- and endometrial cancers with an extreme burden of single nucleotide substitutions. We recently reported that particularly the hereditary POLE exonuclease mutation N363K predisposes in addition to aggressive giant cell glioblastomas. We knocked-in this mutation homozygously into human cell lines and compared its properties to knock-ins of the likewise hereditary POLE L424V mutation and to a complete proofreading-inactivating mutation (exo-null). We found that N363K cells have higher mutation rates as both L424V- or exo-null mutant cells. In contrast to L424V cells, N363K cells expose a growth defect, replication stress and DNA damage. In non-transformed cells, these burdens lead to aneuploidy but macroscopically normal nuclei. In contrast, transformed N363K cells phenocopy the enlarged and disorganized nuclei of giant cell glioblastomas. Taken together, our data characterize a POLE exonuclease domain mutant that not only causes single nucleotide hypermutation, but in addition DNA damage and chromosome instability, leading to an extended tumor spectrum. Our results expand the understanding of the polymerase exonuclease domain and suggest that an assessment of both the mutational potential and the genetic instability might refine classification and treatment of POLE-mutated tumors. Oxford University Press 2023-03-11 /pmc/articles/PMC10006997/ /pubmed/36915289 http://dx.doi.org/10.1093/narcan/zcad011 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle DNA Damage Sensing and Repair
Labrousse, Guillaume
Vande Perre, Pierre
Parra, Genis
Jaffrelot, Marion
Leroy, Laura
Chibon, Frederic
Escudie, Frederic
Selves, Janick
Hoffmann, Jean-Sebastien
Guimbaud, Rosine
Lutzmann, Malik
The hereditary N363K POLE exonuclease mutant extends PPAP tumor spectrum to glioblastomas by causing DNA damage and aneuploidy in addition to increased mismatch mutagenicity
title The hereditary N363K POLE exonuclease mutant extends PPAP tumor spectrum to glioblastomas by causing DNA damage and aneuploidy in addition to increased mismatch mutagenicity
title_full The hereditary N363K POLE exonuclease mutant extends PPAP tumor spectrum to glioblastomas by causing DNA damage and aneuploidy in addition to increased mismatch mutagenicity
title_fullStr The hereditary N363K POLE exonuclease mutant extends PPAP tumor spectrum to glioblastomas by causing DNA damage and aneuploidy in addition to increased mismatch mutagenicity
title_full_unstemmed The hereditary N363K POLE exonuclease mutant extends PPAP tumor spectrum to glioblastomas by causing DNA damage and aneuploidy in addition to increased mismatch mutagenicity
title_short The hereditary N363K POLE exonuclease mutant extends PPAP tumor spectrum to glioblastomas by causing DNA damage and aneuploidy in addition to increased mismatch mutagenicity
title_sort hereditary n363k pole exonuclease mutant extends ppap tumor spectrum to glioblastomas by causing dna damage and aneuploidy in addition to increased mismatch mutagenicity
topic DNA Damage Sensing and Repair
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006997/
https://www.ncbi.nlm.nih.gov/pubmed/36915289
http://dx.doi.org/10.1093/narcan/zcad011
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