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

doi:10.1016/j.isci.2023.106757

TP53BP1, a dual-coding gene, uses promoter switching and translational reinitiation to express a smORF protein

iScience. 2023 Apr 27;26(5):106757. doi: 10.1016/j.isci.2023.106757. eCollection 2023 May 19.

Authors

Marta A Inchingolo¹, Aurélie Diman¹, Maxime Adamczewski^{1

2}, Tom Humphreys^{1

3}, Pascale Jaquier-Gubler¹, Joseph A Curran^{1

4}

Affiliations

¹ Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
² Faculté de Médecine et Pharmacie, Université Grenoble Alpes, Grenoble, France.
³ Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
⁴ Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland.

Abstract

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.

Keywords: Cell biology; Molecular biology; Protein.