TY - JOUR T1 - Small RNA-mediated genomic silencing promotes telomere stability in the absence of telomerase JF - bioRxiv DO - 10.1101/292722 SP - 292722 AU - Charlie Longtine AU - Stephen Frenk AU - Shawn Ahmed Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/04/06/292722.abstract N2 - Telomerase deficiency in human somatic cells results in telomere erosion and senescence. Small RNAs that target telomeres have been observed in diverse organisms but their functions are not well characterized. We define an endogenous small RNA pathway in Caenorhabditis elegans that promotes heterochromatin formation at telomeres via Dicer, the perinuclear Argonaute protein WAGO-1 and the nuclear Argonaute protein HRDE-1. Loss of telomerase induces biogenesis of siRNAs that target the telomeric lncRNA TERRA, whereas loss of both telomerase and small RNA-mediated telomeric silencing induces TERRA expression, DNA damage, and an accelerated sterility phenotype. These phenotypes can be rescued by exogenous telomeric siRNAs or by loss of the DNA damage response protein EXO-1. Thus, endogenous siRNAs interact with TERRA to promote heterochromatin formation in a manner that is critical for the stability of naturally eroding telomeres. We propose that small RNA-mediated genome silencing could be broadly relevant to regulation of proliferative aging. ER -