Small RNA-mediated genomic silencing promotes telomere stability in the absence of telomerase

We define an endogenous small RNA pathway in Caenorhabditis elegans that protects telomeres via Dicer, the perinuclear Argonaute protein WAGO-1, the nuclear Argonaute protein HRDE-1, and the HP1 protein HPL-2 that stabilizes the heterochromatin mark H3K9me2. Loss of telomerase induces biogenesis of subtelomeric small RNAs, whereas loss of both telomerase and small RNA-mediated genome silencing induces expression of the telomeric lncRNA TERRA, DNA damage, and accelerated sterility. These phenotypes were rescued by exogenous telomeric small RNAs and by loss of the DNA damage response protein EXO-1. Although ATRX promotes heterochromatin deposition and is lost in human tumors that maintain their telomeres via ALT, we detected only a modest role for the C. elegans ATRX ortholog XNP-1 in telomere protection in the absence of telomerase. Moreover, neither XNP-1 nor small RNA factors that promote telomere stability in the absence of telomerase repress ALT in C. elegans. We propose that small RNA-mediated heterochromatin formation and telomerase function redundantly to repress a form of telomeric DNA damage that induces TERRA expression. We conclude that small RNA-mediated genome silencing promotes telomere stability in the absence of telomerase. Article SummaryWe found that a number of small RNA biogenesis factors and heterochromatin proteins promoted telomere stability in the absence of telomerase. The telomeric non-coding RNA TERRA and DNA damage signaling were induced upon loss of small RNAs and telomerase, indicating that small RNAs directly or indirectly repress TERRA expression and telomeric DNA damage, both of which were suppressed when telomerase acts to heal telomeric damage. These findings reveal a functional interaction between small RNAs and telomere biology that is relevant to the fields of aging, genome stability and small RNAs.