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Multinucleation associated DNA damage blocks proliferation in p53-compromised cells

Nuclear atypia is one of the hallmarks of cancers. Here, we perform single-cell tracking studies to determine the immediate and long-term impact of nuclear atypia. Tracking the fate of newborn cells exhibiting nuclear atypia shows that multinucleation, unlike other forms of nuclear atypia, blocks pr...

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Autores principales: Hart, Madeleine, Adams, Sophie D., Draviam, Viji M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035210/
https://www.ncbi.nlm.nih.gov/pubmed/33837239
http://dx.doi.org/10.1038/s42003-021-01979-5
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author Hart, Madeleine
Adams, Sophie D.
Draviam, Viji M.
author_facet Hart, Madeleine
Adams, Sophie D.
Draviam, Viji M.
author_sort Hart, Madeleine
collection PubMed
description Nuclear atypia is one of the hallmarks of cancers. Here, we perform single-cell tracking studies to determine the immediate and long-term impact of nuclear atypia. Tracking the fate of newborn cells exhibiting nuclear atypia shows that multinucleation, unlike other forms of nuclear atypia, blocks proliferation in p53-compromised cells. Because ~50% of cancers display compromised p53, we explored how multinucleation blocks proliferation. Multinucleation increases 53BP1-decorated nuclear bodies (DNA damage repair platforms), along with a heterogeneous reduction in transcription and protein accumulation across the multi-nucleated compartments. Multinucleation Associated DNA Damage associated with 53BP1-bodies remains unresolved for days, despite an intact NHEJ machinery that repairs laser-induced DNA damage within minutes. Persistent DNA damage, a DNA replication block, and reduced phospho-Rb, reveal a novel replication stress independent cell cycle arrest caused by mitotic lesions. These findings call for segregating protective and prohibitive nuclear atypia to inform therapeutic approaches aimed at limiting tumour heterogeneity.
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spelling pubmed-80352102021-04-27 Multinucleation associated DNA damage blocks proliferation in p53-compromised cells Hart, Madeleine Adams, Sophie D. Draviam, Viji M. Commun Biol Article Nuclear atypia is one of the hallmarks of cancers. Here, we perform single-cell tracking studies to determine the immediate and long-term impact of nuclear atypia. Tracking the fate of newborn cells exhibiting nuclear atypia shows that multinucleation, unlike other forms of nuclear atypia, blocks proliferation in p53-compromised cells. Because ~50% of cancers display compromised p53, we explored how multinucleation blocks proliferation. Multinucleation increases 53BP1-decorated nuclear bodies (DNA damage repair platforms), along with a heterogeneous reduction in transcription and protein accumulation across the multi-nucleated compartments. Multinucleation Associated DNA Damage associated with 53BP1-bodies remains unresolved for days, despite an intact NHEJ machinery that repairs laser-induced DNA damage within minutes. Persistent DNA damage, a DNA replication block, and reduced phospho-Rb, reveal a novel replication stress independent cell cycle arrest caused by mitotic lesions. These findings call for segregating protective and prohibitive nuclear atypia to inform therapeutic approaches aimed at limiting tumour heterogeneity. Nature Publishing Group UK 2021-04-09 /pmc/articles/PMC8035210/ /pubmed/33837239 http://dx.doi.org/10.1038/s42003-021-01979-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hart, Madeleine
Adams, Sophie D.
Draviam, Viji M.
Multinucleation associated DNA damage blocks proliferation in p53-compromised cells
title Multinucleation associated DNA damage blocks proliferation in p53-compromised cells
title_full Multinucleation associated DNA damage blocks proliferation in p53-compromised cells
title_fullStr Multinucleation associated DNA damage blocks proliferation in p53-compromised cells
title_full_unstemmed Multinucleation associated DNA damage blocks proliferation in p53-compromised cells
title_short Multinucleation associated DNA damage blocks proliferation in p53-compromised cells
title_sort multinucleation associated dna damage blocks proliferation in p53-compromised cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035210/
https://www.ncbi.nlm.nih.gov/pubmed/33837239
http://dx.doi.org/10.1038/s42003-021-01979-5
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