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/DENRTma22 also 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.
Highlights
The bulk of the genome is duplicated precisely once each cell cycle but telomeres are replicated differently
We show that levels of Stn1 in yeast and human cells are reduced by the presence of an upstream overlapping open reading frame
We show that the overlapping open reading frame (oORF) reduces Stn1 levels by stimulating nonsense mediated mRNA decay and by reducing translation
Summary
The bulk of the genome is duplicated precisely once each cell cycle but telomeres are replicated differently. DNA polymerases cannot replicate the ends of linear molecules and different strategies are needed to replicate telomeric DNA. The majority of eukaryotes use a reverse transcriptase based enzyme, telomerase, to elongate DNA at telomeric ends. Most human somatic cells express low levels of telomerase, the telomeres shorten with each cell cycle, eventually leading to cell cycle arrest and senescence [1]. Many cancers over-express telomerase and hyper-elongate telomeres, a process that facilitates uncontrolled cell division. Point mutations in the telomerase (TERT) promoter, which increase TERT expression, are the most commonly identified non-coding mutations found in human cancer [2, 3]
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