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Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis
Melanomas and other solid tumors commonly have increased ploidy, with near-tetraploid karyotypes being most frequently observed. Such karyotypes have been shown to arise through whole-genome doubling events that occur during early stages of tumor progression. The generation of tetraploid cells via w...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287415/ https://www.ncbi.nlm.nih.gov/pubmed/35840569 http://dx.doi.org/10.1038/s41467-022-31899-9 |
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author | Darp, Revati Vittoria, Marc A. Ganem, Neil J. Ceol, Craig J. |
author_facet | Darp, Revati Vittoria, Marc A. Ganem, Neil J. Ceol, Craig J. |
author_sort | Darp, Revati |
collection | PubMed |
description | Melanomas and other solid tumors commonly have increased ploidy, with near-tetraploid karyotypes being most frequently observed. Such karyotypes have been shown to arise through whole-genome doubling events that occur during early stages of tumor progression. The generation of tetraploid cells via whole-genome doubling is proposed to allow nascent tumor cells the ability to sample various pro-tumorigenic genomic configurations while avoiding the negative consequences that chromosomal gains or losses have in diploid cells. Whereas a high prevalence of whole-genome doubling events has been established, the means by which whole-genome doubling arises is unclear. Here, we find that BRAF(V600E), the most common mutation in melanomas, can induce whole-genome doubling via cytokinesis failure in vitro and in a zebrafish melanoma model. Mechanistically, BRAF(V600E) causes decreased activation and localization of RhoA, a critical cytokinesis regulator. BRAF(V600E) activity during G1/S phases of the cell cycle is required to suppress cytokinesis. During G1/S, BRAF(V600E) activity causes inappropriate centriole amplification, which is linked in part to inhibition of RhoA and suppression of cytokinesis. Together these data suggest that common abnormalities of melanomas linked to tumorigenesis – amplified centrosomes and whole-genome doubling events – can be induced by oncogenic BRAF and other mutations that increase RAS/MAPK pathway activity. |
format | Online Article Text |
id | pubmed-9287415 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-92874152022-07-17 Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis Darp, Revati Vittoria, Marc A. Ganem, Neil J. Ceol, Craig J. Nat Commun Article Melanomas and other solid tumors commonly have increased ploidy, with near-tetraploid karyotypes being most frequently observed. Such karyotypes have been shown to arise through whole-genome doubling events that occur during early stages of tumor progression. The generation of tetraploid cells via whole-genome doubling is proposed to allow nascent tumor cells the ability to sample various pro-tumorigenic genomic configurations while avoiding the negative consequences that chromosomal gains or losses have in diploid cells. Whereas a high prevalence of whole-genome doubling events has been established, the means by which whole-genome doubling arises is unclear. Here, we find that BRAF(V600E), the most common mutation in melanomas, can induce whole-genome doubling via cytokinesis failure in vitro and in a zebrafish melanoma model. Mechanistically, BRAF(V600E) causes decreased activation and localization of RhoA, a critical cytokinesis regulator. BRAF(V600E) activity during G1/S phases of the cell cycle is required to suppress cytokinesis. During G1/S, BRAF(V600E) activity causes inappropriate centriole amplification, which is linked in part to inhibition of RhoA and suppression of cytokinesis. Together these data suggest that common abnormalities of melanomas linked to tumorigenesis – amplified centrosomes and whole-genome doubling events – can be induced by oncogenic BRAF and other mutations that increase RAS/MAPK pathway activity. Nature Publishing Group UK 2022-07-15 /pmc/articles/PMC9287415/ /pubmed/35840569 http://dx.doi.org/10.1038/s41467-022-31899-9 Text en © The Author(s) 2022 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 Darp, Revati Vittoria, Marc A. Ganem, Neil J. Ceol, Craig J. Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis |
title | Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis |
title_full | Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis |
title_fullStr | Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis |
title_full_unstemmed | Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis |
title_short | Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis |
title_sort | oncogenic braf induces whole-genome doubling through suppression of cytokinesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287415/ https://www.ncbi.nlm.nih.gov/pubmed/35840569 http://dx.doi.org/10.1038/s41467-022-31899-9 |
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