Abstract
The long noncoding telomeric repeat containing RNA (TERRA) is expressed at chromosome ends. TERRA upregulation upon experimental manipulation or in ICF (immunodeficiency, centromeric instability, facial anomalies) patients correlates with short telomeres. To study the mechanism of telomere length control by TERRA in Saccharomyces cerevisiae, we mapped the transcriptional start site of TERRA at telomere 1L and inserted a doxycycline regulatable promoter upstream. Induction of TERRA transcription led to telomere shortening of 1L but not of other chromosome ends. TERRA interacts with the Exo1-inhibiting Ku70/80 complex, and deletion of EXO1 but not MRE11 fully suppressed the TERRA–mediated short telomere phenotype in presence and absence of telomerase. Thus TERRA transcription facilitates the 5′-3′ nuclease activity of Exo1 at chromosome ends, providing a means to regulate the telomere shortening rate. Thereby, telomere transcription can regulate cellular lifespan through modulation of chromosome end processing activities.
Highlights
The ends of eukaryotic chromosomes, known as telomeres, consist of simple DNA repeats, specialized proteins and long noncoding RNAs [1]
Telomere length is a balance between the rate of telomere shortening, which occurs due to the end replication problem and the nucleolytic processing of chromosome ends and telomere elongation which is mediated by the cellular reverse transcriptase telomerase [4,5,6,7,8]
Telomeres protect chromosome ends from end fusion and end degradation, and they regulate cellular lifespan
Summary
The ends of eukaryotic chromosomes, known as telomeres, consist of simple DNA repeats, specialized proteins and long noncoding RNAs [1]. Telomere length regulates cellular lifespan in humans in which telomerase is turned off in most somatic cells [3]. Telomere length is a balance between the rate of telomere shortening, which occurs due to the end replication problem and the nucleolytic processing of chromosome ends and telomere elongation which is mediated by the cellular reverse transcriptase telomerase [4,5,6,7,8]. The preferential recruitment and activation of telomerase to shorter telomeres is mediated by the Tel checkpoint kinase and Tbf, a protein which binds to the subtelomeric DNA sequences present at natural chromosome ends [9,10,11,12,13]. The telomere shortening rate in the absence of telomerase is constant and appears length-independent [5]
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