A small protein, derived from an alternative 53BP1 promoter transcript and expressed via translational reinitiation on an internal overlapping ORF, modulates proteasome activity

The complexity of the metazoan proteome is significantly increased by the expression of small proteins (<100 aas) derived from smORFs within lncRNAs, uORFs, 3’ UTRs and, more rarely, reading frames overlapping the CDS. These smORF encoded proteins (SEPs) can have diverse roles, ranging from the regulation of cellular physiological to essential developmental functions. We report the characterisation of a new member of this protein family, SEP53BP1, derived from a small internal ORF that overlaps the CDS that encodes 53BP1. Its expression is coupled to the utilisation of an alternative, cell-type specific, promoter coupled to translational reinitiation events mediated by a uORF in the alternative 5’ TL of the mRNA. The uORF-mediated initiation at the internal AUG53BP1 is conserved in metazoan species ranging from human to zebrafish. As such, it couples SEP53BP1 expression to the integrated stress response (ISR). We demonstrate that one function of this protein is to interact with, and stimulate, the activity of the 26S proteasome. As such, it opens the door to new approaches in the treatment of clinical conditions that arise due to the accumulation of toxic intracellular protein aggregates

• Publication year

  2021

• Venue

  bioRxiv

• Publication date

  2021-08-23

• Fields of study

  Biology

• Identifiers
  DOI 10.1101/2021.08.23.457304
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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