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Systematic characterization of mutations altering protein degradation in human cancers.

ABSTRACT: The ubiquitin-proteasome system (UPS) is the primary route for selective protein degradation in human cells. The UPS is an attractive target for novel cancer therapies, but the precise UPS genes and substrates important for cancer growth are incompletely understood. Leveraging multi-omics data across more than 9,000 human tumors and 33 cancer types, we found that over 19% of all cancer driver genes affect UPS function. We implicate transcription factors as important substrates and show that c-Myc stability is modulated by CUL3. Moreover, we developed a deep learning model (deepDegron) to identify mutations that result in degron loss and experimentally validated the prediction that gain-of-function truncating mutations in GATA3 and PPM1D result in increased protein stability. Last, we identified UPS driver genes associated with prognosis and the tumor microenvironment. This study demonstrates the important role of UPS dysregulation in human cancer and underscores the potential therapeutic utility of targeting the UPS.

SUBMITTER: Tokheim C

PROVIDER: S-EPMC9245451 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Systematic Characterization of Mutations Altering Protein Degradation in Human Cancers

Project description:The Ubiquitin-Proteasome System (UPS) is the primary route for selective protein degradation in human cells. We implicate transcription factors as important substrates. By developing a deep learning model (deepDegron) to identify mutations that result in degron loss, and experimentally validated predictions that gain-of-function truncating mutations in GATA3 result in increased protein stability. We profiled the DNA binding by ChIP-seq of GATA3 in response to point mutations of the implicated degron. We found an increase in DNA binding, with up-regulating peaks preferentially found near estrogen signaling related genes. To serve as control, we include GATA3 with a c-terminal FLAG-tag that would stabilize GATA3 regardless of mutation status. No significant enrichment was observed in the control.

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Systematic Characterization of Mutations Altering Protein Degradation in Human Cancers

Project description:Systematic Characterization of Mutations Altering Protein Degradation in Human Cancers

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Missense mutations in the human SDHB gene increase protein degradation without altering intrinsic enzymatic function.

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Identification and characterization of retinoblastoma gene mutations disturbing apoptosis in human breast cancers.

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