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Overlapping open reading frames strongly reduce human and yeast STN1 gene expression and affect telomere function

Lookup NU author(s): Victoria Torrance, Professor David Lydall

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

The levels of telomeric proteins, such as telomerase, can have profound effects on telomere function, cell division and human disease. Here we demonstrate how levels of Stn1, a component of the conserved telomere capping CST (Cdc13, Stn1, Ten1) complex, are tightly regulated by an upstream overlapping open reading frame (oORF). In budding yeast inactivation of the STN1 oORF leads to a 10-fold increase in Stn1 levels, reduced telomere length, suppression of cdc13-1 and enhancement of yku70Δ growth defects. The STN1 oORF impedes translation of the main ORF and reduces STN1 mRNA via the nonsense mediated mRNA decay (NMD) pathway. Interestingly, the homologs of the translation re-initiation factors, MCT-1Tma20/DENRTma22also reduce Stn1 levels via the oORF. Human STN1 also contains oORFs, which reduce expression, demonstrating that oORFs are a conserved mechanism for reducing Stn1 levels. Bioinformatic analyses of the yeast and human transcriptomes show that oORFs are more underrepresented than upstream ORFs (uORFs) and associated with lower protein abundance. We propose that oORFs are an important mechanism to control expression of a subset of the proteome.

Publication metadata

Author(s): Torrance V, Lydall D

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2018

Volume: 14

Issue: 8

Online publication date: 01/08/2018

Acceptance date: 28/06/2018

Date deposited: 23/11/2018

ISSN (print): 1553-7390

ISSN (electronic): 1553-7404

Publisher: Public Library of Science

URL: https://doi.org/10.1371/journal.pgen.1007523

DOI: 10.1371/journal.pgen.1007523

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