Genetic fusions favor tumorigenesis through degron loss in oncogenes.
Nat Commun
; 12(1): 6704, 2021 11 18.
Article
em En
| MEDLINE
| ID: mdl-34795215
ABSTRACT
Chromosomal rearrangements can generate genetic fusions composed of two distinct gene sequences, many of which have been implicated in tumorigenesis and progression. Our study proposes a model whereby oncogenic gene fusions frequently alter the protein stability of the resulting fusion products, via exchanging protein degradation signal (degron) between gene sequences. Computational analyses of The Cancer Genome Atlas (TCGA) identify 2,406 cases of degron exchange events and reveal an enrichment of oncogene stabilization due to loss of degrons from fusion. Furthermore, we identify and experimentally validate that some recurrent fusions, such as BCR-ABL, CCDC6-RET and PML-RARA fusions, perturb protein stability by exchanging internal degrons. Likewise, we also validate that EGFR or RAF1 fusions can be stabilized by losing a computationally-predicted C-terminal degron. Thus, complementary to enhanced oncogene transcription via promoter swapping, our model of degron loss illustrates another general mechanism for recurrent fusion proteins in driving tumorigenesis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oncogenes
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Proteínas de Fusão Oncogênica
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Motivos de Aminoácidos
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Carcinogênese
/
Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
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Male
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article