TERRA Biogenesis, telomere association and displacement from telomeres. TERRA Biogenesis (upper panel)—TERRA is an RNAPII-dependent transcript whose transcription initiates within the subtelomeric sequences and proceeds into the telomeric tract. Human TRF1 may promote transcription through the telomere tract through its association with RNAPII. A fraction of TERRA is polyadenylated through the canonical poly(A) polymerase, Pap1. The 5′-end structure that exists on TERRA molecules has not yet been reported. Telomere association (middle panel)—TERRA colocalizes with telomeres as visualized by RNA-FISH experiments on human interphase and metaphase chromosomes. Indirect evidence suggests that at least a portion of TERRA is bound to telomeres through base pairing with telomeric DNA. Undefined RNA–protein interactions or intermolecular G-quadruplex structures (Gquad) may also tether TERRA to telomeric DNA. Telomere removal and degradation (lower panel)—the 5′ to 3′ exonuclease, Rat1, directly degrades TERRA molecules and can itself be found associated with telomeres. Rat1 can degrade its other target RNAs in a co-transcriptional manner (as depicted here), whether TERRA is degraded by Rat1 in a similar manner has yet to be determined. The poly(A) polymerase, Trf4, also contributes to TERRA degradation, although likely as a minor contributor compared with Rat1. The NMD factors, UPF1, SMG1 and EST1A/SMG6, all contribute to TERRA removal from telomeres. Inhibition of any of these factors results in both more and brighter TERRA foci, although overall TERRA levels as assessed by northern blot analysis remain largely unchanged. RNaseH overexpression also reduces cellular TERRA levels when Rat1 function is impaired.
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