Identification of the RNA dependent RNA polymerase and mechanism of chromatin maintenance

Constitutive expression of telomerase in human cells prevents the onset of senescence and crisis by maintaining telomere homeostasis. However, recent evidence suggests that the human telomerase catalytic subunit (hTERT) contributes to cell physiology independent of its ability to elongate telomeres. Here we show that hTERT interacts with the RNA component of mitochondrial RNA processing endoribonuclease (RMRP), a gene that is mutated in the inherited pleiotropic syndrome Cartilage-Hair Hypoplasia. hTERT and RMRP form an RNA dependent RNA polymerase (RdRP) and produce double-stranded RNAs that can be processed into small interfering RNA in a Dicer dependent manner. Moreover, these endogenous RMRP-specific siRNAs are associated with human Ago2. These observations identify a mammalian RdRP composed of hTERT in complex with RMRP that participates in gene silencing through the production of endogenous siRNA.