Investigating the Aggregation and Prionogenic Properties of Human Cancer-Related Proteins.

IF 3.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Dustin Goncharoff, Zhiqiang Du, Shriram Venkatesan, Brandon Cho, Jenny Zhao, Milad J Alasady, Dalton Huey, Hannah Ma, Jake Rosenthal, Alexander Turenitsa, Coral Feldman, Randal Halfmann, Marc L Mendillo, Liming Li
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引用次数: 0

Abstract

Cancer encompasses a range of severe diseases characterized by uncontrolled cell growth and the potential for metastasis. Understanding the mechanism underlying tumorigenesis has been a central focus of cancer research. Self-propagating protein aggregates, known as prions, are linked to various biological functions and diseases, particularly those related to mammalian neurodegeneration. However, it remains unclear whether prion-like mechanisms contribute to tumorigenesis and cancer. Using a combined approach of algorithmic predictions, alongside genetic and biochemical experimentation, we identified numerous cancer-associated proteins prone to aggregation, many of which contain prion-like domains (PrLDs). These predictions were experimentally validated for both aggregation and prion-formation. We demonstrate that several PrLDs undergo nucleation-limited amyloid formation, which can alter protein activity in a mitotically heritable fashion. These include SSXT, a subunit of the chromatin-remodeling BAF (hSWI/SNF) complexes; CLOCK, a core component of the circadian clock; and EPN4, a clathrin-interacting protein involved in protein trafficking between the trans-Golgi network and endosomes. The prions formed by these PrLDs occurred in multiple variants and depended on Hsp104, a molecular chaperone with disaggregase activity. Our results reveal an inherent tendency for prion-like aggregation in human cancer-associated proteins, suggesting a potential role for such aggregation in the epigenetic changes driving tumorigenesis.

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来源期刊
Molecular and Cellular Biology
Molecular and Cellular Biology 生物-生化与分子生物学
CiteScore
9.80
自引率
1.90%
发文量
120
审稿时长
1 months
期刊介绍: Molecular and Cellular Biology (MCB) showcases significant discoveries in cellular morphology and function, genome organization, regulation of genetic expression, morphogenesis, and somatic cell genetics. The journal also examines viral systems, publishing papers that emphasize their impact on the cell.
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