Protein chimerism: Novel source of protein diversity in humans adds complexity to bottom-up proteomics

Authors

  • Juan Casado-Vela,

    Corresponding author
    • Centro Nacional de Biotecnología. Lab 115. Dpt. Biología Molecular y Celular, Spanish National Research Council (CSIC), Madrid, Spain
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  • Juan Carlos Lacal,

    Corresponding author
    • Translational Oncology Unit, Instituto de Investigaciones Biomédicas ‘Alberto Sols’, Spanish National Research Council (CSIC-UAM), Madrid, Spain
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  • Felix Elortza

    Corresponding author
    • Proteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Technology Park of Bizkaia, Derio, Spain
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  • Colour Online: See the article online to view Figs. 1 and 2 in colour.

Correspondence: Dr. Juan Casado-Vela, Centro Nacional de Biotecnología, Lab 115, Dpt. Biología Molecular y Celular, Spanish National Research Council (CSIC), 28049 Madrid, Spain.

E-mail: jcasado@cnb.csic.es

Fax: +34-915854401

Additional corresponding authors: Dr. Felix Elortza, E-mail: felortza@cicbiogune.es; Dr. Juan Carlos Lacal, E-mail: jclacal@iib.uam.es.

Abstract

Three main molecular mechanisms are considered to contribute expanding the repertoire and diversity of proteins present in living organisms: first, at DNA level (gene polymorphisms and single nucleotide polymorphisms); second, at messenger RNA (pre-mRNA and mRNA) level including alternative splicing (also termed differential splicing or cis-splicing); finally, at the protein level mainly driven through PTM and specific proteolytic cleavages. Chimeric mRNAs constitute an alternative source of protein diversity, which can be generated either by chromosomal translocations or by trans-splicing events. The occurrence of chimeric mRNAs and proteins is a frequent event in cells from the immune system and cancer cells, mainly as a consequence of gene rearrangements. Recent reports support that chimeric proteins may also be expressed at low levels under normal physiological circumstances, thus, representing a novel source of protein diversity. Notably, recent publications demonstrate that chimeric protein products can be successfully identified through bottom-up proteomic analyses. Several questions remain unsolved, such as the physiological role and impact of such chimeric proteins or the potential occurrence of chimeric proteins in higher eukaryotic organisms different from humans. The occurrence of chimeric proteins certainly seems to be another unforeseen source of complexity for the proteome. It may be a process to take in mind not only when performing bottom-up proteomic analyses in cancer studies but also in general bottom-up proteomics experiments.

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