The RNA interactome of human telomerase RNA reveals a coding-independent role for a histone mRNA in telomere homeostasis

Abstract

Telomerase RNA (TR) provides the template for DNA repeat synthesis at telomeres and is essential for genome stability in continuously dividing cells. We mapped the RNA interactome of human TR (hTR) and identified a set of non-coding and coding hTR-interacting RNAs, including the histone 1C mRNA (HIST1H1C). Disruption of the hTR-HIST1H1C RNA association resulted in markedly increased telomere elongation without affecting telomerase enzymatic activity. Conversely, over-expression of HIST1H1C led to telomere attrition. By using a combination of mutations to disentangle the effects of histone 1 RNA synthesis, protein expression, and hTR interaction, we show that HIST1H1C RNA negatively regulates telomere length independently of its protein coding potential. Taken together, our data provide important insights into a surprisingly complex hTR-RNA interaction network and define an unexpected non-coding RNA role for HIST1H1C in regulating telomere length homeostasis, thus offering a glimpse into the mostly uncharted, vast space of non-canonical messenger RNA functions.

How RNAi machinery enters the world of telomerase

“…We showed that disruption of TERC regions complementary to terc-sRNA impaired association between AGO2 and TERC. In line with our data, it was recently shown that TERC can interact with different RNA molecules by direct RNA-RNA base pairing and predicted interaction sites fall mostly within regions spanning terc-sRNA target sites in CR4/CR5 and in the TBE domains, suggesting that these regions are prone to form RNA duplexes [91]. Therefore, we hypothesize that terc-sRNA might recognize TERC by base complementarity and recruit AGO2 to TERC.…”

Coding or Noncoding, the Converging Concepts of RNAs

“…Aside from the protein-related product, a 15-nt long region in the ORF region (nt334–nt348) is attributed to HIST1H1C -mRNA-mediated biological activity, through complementation with the terminal stem-loop sequence of the P6b region of hTR, in a base-pairing pattern. These results extend the functional potency of mRNA ORF regions in a non-traditional and noncoding direction (Ivanyi-Nagy et al, 2018).…”

Ratiometric Electrochemical Sensing Strategy for the Ultrasensitive Detection of Telomerase Activity

“…Human telomerase is a ribonucleoprotein complex with an endogenous RNA template, which catalyzes the extension of hexamer DNA repeats . In a majority of human cancers, telomerase is upregulated or reactivated, which leads to indefinite proliferation of cancer cells .…”