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bioRxiv · 10.1101/2021.04.08.439023

Oncogenic BRAF Induces Whole-Genome Doubling Through Suppression of Cytokinesis

Darp, R.·Vittoria, M. A.·Ganem, N. J.·Ceol, C. J.
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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 BRAFV600E, the most common mutation in melanomas, can induce whole-genome doubling via cytokinesis failure in vitro and in a zebrafish melanoma model. Mechanistically, BRAFV600E causes decreased activation and localization of RhoA, a critical cytokinesis regulator. BRAFV600E activity during G1/S phases of the cell cycle is required to suppress cytokinesis. During G1/S, BRAFV600E 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 SignificanceWhole-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 BRAFV600E can induce whole-genome doubling through suppression of cytokinesis, and BRAFV600E-induced whole-genome doubling can occur in melanocytes and be present in nascent melanoma cells upon tumorigenesis.

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Darp, R., Vittoria, M. A., Ganem, N. J., Ceol, C. J.. 2021-04-09. Oncogenic BRAF Induces Whole-Genome Doubling Through Suppression of Cytokinesis. https://doi.org/10.1101/2021.04.08.439023

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