Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1784905409427931136 |
---|---|
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. |
format | Online Article Text |
id | pubmed-10006997 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT labrousseguillaume thehereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT vandeperrepierre thehereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT parragenis thehereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT jaffrelotmarion thehereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT leroylaura thehereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT chibonfrederic thehereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT escudiefrederic thehereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT selvesjanick thehereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT hoffmannjeansebastien thehereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT guimbaudrosine thehereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT lutzmannmalik thehereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT labrousseguillaume hereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT vandeperrepierre hereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT parragenis hereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT jaffrelotmarion hereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT leroylaura hereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT chibonfrederic hereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT escudiefrederic hereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT selvesjanick hereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT hoffmannjeansebastien hereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT guimbaudrosine hereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity AT lutzmannmalik hereditaryn363kpoleexonucleasemutantextendsppaptumorspectrumtoglioblastomasbycausingdnadamageandaneuploidyinadditiontoincreasedmismatchmutagenicity |