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Molecular mechanisms of non-genetic aberrant peptide production in cancer

Abstract

The cancer peptidome has long been known to be altered by genetic mutations. However, more recently, non-genetic polypeptide mutations have also been related to cancer cells. These non-genetic mutations occur post-t30ranscriptionally, leading to the modification of the peptide primary structure, while the corresponding genes remain unchanged. Three main processes participate in the production of these aberrant proteins: mRNA alternative splicing, mRNA editing, and mRNA aberrant translation. In this review, we summarize the molecular mechanisms underlying these processes and the recent findings on the functions of the aberrant proteins, as well as their exploitability as new therapeutic targets due to their specific enrichment in cancer cells. These non-genetic aberrant polypeptides represent a source of novel cancer cell targets independent from their level of mutational burden, still to be exhaustively explored.

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Fig. 1: In cancer cells, aberrant translation, alternative splicing, and increased RNA editing contribute to the production of aberrant polypeptides (marked with red dots).
Fig. 2: Splicing mechanism.
Fig. 3: Graphical representation of alternative splicing patterns.
Fig. 4: Chemical properties of A-to-I and C-to-U editing.

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Conceptualization: DW, AF, RA; writing—original draft preparation: DW, AF; figure preparation: DW; writing—review and final editing: DW, AF, RA.

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Correspondence to Reuven Agami.

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The authors declare no competing interests. RA is supported by the Dutch Cancer Society (KWF project 13647), the European Research Council (ERC-2018-ADG - GA 832844), and the AvL Foundation.

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Wernaart, D., Fumagalli, A. & Agami, R. Molecular mechanisms of non-genetic aberrant peptide production in cancer. Oncogene 43, 2053–2062 (2024). https://doi.org/10.1038/s41388-024-03069-2

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