TP53BP1, a dual-coding gene, uses promoter switching and translational reinitiation to express a smORF protein
Marta A. Inchingolo,
Aurélie Diman,
Maxime Adamczewski,
Tom Humphreys,
Pascale Jaquier-Gubler,
Joseph A. Curran
Affiliations
Marta A. Inchingolo
Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
Aurélie Diman
Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
Maxime Adamczewski
Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Faculté de Médecine et Pharmacie, Université Grenoble Alpes, Grenoble, France
Tom Humphreys
Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
Pascale Jaquier-Gubler
Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland
Joseph A. Curran
Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland; Corresponding author
Summary: The complexity of the metazoan proteome is significantly increased by the expression of small proteins (<100 aa) derived from smORFs within lncRNAs, uORFs, 3′ UTRs and, reading frames overlapping the CDS. These smORF encoded proteins (SEPs) have diverse roles, ranging from the regulation of cellular physiological to essential developmental functions. We report the characterization of a new member of this protein family, SEP53BP1, derived from a small internal ORF that overlaps the CDS encoding 53BP1. Its expression is coupled to the utilization of an alternative, cell-type specific promoter coupled to translational reinitiation events mediated by a uORF in the alternative 5′ TL of the mRNA. This uORF-mediated reinitiation at an internal ORF is also observed in zebrafish. Interactome studies indicate that the human SEP53BP1 associates with components of the protein turnover pathway including the proteasome, and the TRiC/CCT chaperonin complex, suggesting that it may play a role in cellular proteostasis.
