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Title:
Systematic analysis of alterations in the ubiquitin proteolysis system reveals its contribution to driver mutations in cancer | Nature Cancer
Description:
E3 ligases and degrons, the sequences they recognize in target proteins, are key parts of the ubiquitin-mediated proteolysis system. There are several examples of alterations of these two components of the system that have a role in cancer. Here we uncover the landscape of the contribution of such alterations to tumorigenesis across cancer types. We first systematically identified new instances of degrons across the human proteome by using a random forest classifier and validated the functionality of a dozen of them, exploiting somatic mutations across >7,000 tumors. We detected signals of positive selection across known and new degron instances. Our results reveal that several oncogenes are frequently targeted by mutations that affect the sequence of their degrons or their cognate E3 ubiquitin ligases, causing an abnormal increase in their protein abundance. Overall, an important number of driver mutations across primary tumors affect either degrons or E3-ubiquitin ligases. Martínez-Jiménez et al. report how disruption of the ubiquitin–proteasome system affects cancer, estimating that >10% of driver mutations involve alterations in genes relevant in ubiquitin-mediated proteolysis, including E3 ligases and their targets.
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nature portfolio journals org/account/user/bbglab/projects/pd permissions reprints nature portfolio privacy policy interactive scientific computing advertising supplementary table 2 middle men abel gonzalez-perez european research council tcga research network broad institute portal 5-fold cross-validation nature+ nature nuria lopez-bigas supplementary data ubiquitin-mediated proteolysis system ubiquitin proteasome system—implications protein–protein interaction networks βtrcp2/fbxw11 ubiquitin ligase keap1–cul3 e3 ligase stabilizes c-myc packt publishing chromatin regulatory factors pan-cancer gene fusions e3-ubiquitin ligases cancer francisco martínez-jiménez exploratory research tailed mann-whitney test including development tailed mann-whitney tests social media reilly media article martínez-jiménez human tumor rna-seq e3 ubiquitin ligase tcpa portal research ubiquitin-mediated proteolysis permissions gonzalez-perez gonzalez-perez tcga pan-cancer cohort springerlink instant access ubiquitin–proteasome system development de novo degrons cancer driver genes
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headline:Systematic analysis of alterations in the ubiquitin proteolysis system reveals its contribution to driver mutations in cancer
description:E3 ligases and degrons, the sequences they recognize in target proteins, are key parts of the ubiquitin-mediated proteolysis system. There are several examples of alterations of these two components of the system that have a role in cancer. Here we uncover the landscape of the contribution of such alterations to tumorigenesis across cancer types. We first systematically identified new instances of degrons across the human proteome by using a random forest classifier and validated the functionality of a dozen of them, exploiting somatic mutations across >7,000 tumors. We detected signals of positive selection across known and new degron instances. Our results reveal that several oncogenes are frequently targeted by mutations that affect the sequence of their degrons or their cognate E3 ubiquitin ligases, causing an abnormal increase in their protein abundance. Overall, an important number of driver mutations across primary tumors affect either degrons or E3-ubiquitin ligases. MartÃnez-Jiménez et al. report how disruption of the ubiquitinâproteasome system affects cancer, estimating that >10% of driver mutations involve alterations in genes relevant in ubiquitin-mediated proteolysis, including E3 ligases and their targets.
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