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• W4240658270 abstract "Abstract 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. Statement of Significance Whole-genome doubling is prevalent in many types of solid tumors and important in shaping tumor genomes, yet the causes of whole-genome doubling are not well understood. Here, we discover that oncogenic BRAF V600E can induce whole-genome doubling through suppression of cytokinesis, and BRAF V600E -induced whole-genome doubling can occur in melanocytes and be present in nascent melanoma cells upon tumorigenesis." @default.
• W4240658270 created "2022-05-12" @default.
• W4240658270 creator A5034685016 @default.
• W4240658270 creator A5036802615 @default.
• W4240658270 creator A5061976377 @default.
• W4240658270 creator A5076079215 @default.
• W4240658270 date "2021-04-09" @default.
• W4240658270 modified "2023-10-03" @default.
• W4240658270 title "Oncogenic BRAF Induces Whole-Genome Doubling Through Suppression of Cytokinesis" @default.
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• W4240658270 doi "https://doi.org/10.1101/2021.04.08.439023" @default.
• W4240658270 hasPublicationYear "2021" @default.
• W4240658270 type Work @default.
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