The Telomeric Noncoding RNA TERRA Regulates Telomere Stability

Telomeric repeat–containing noncoding RNAs (TERRA) are long noncoding RNAs that contain the canonical telomeric repeat sequence UUAGGG and have been found to associate with telomere ends in mammals and have been linked to cancer, cellular senescence, and aging. TERRA have proposed roles in the protection of telomere ends, regulation of telomere length, recombination between telomere ends, and recruitment of chromatin factors, but the specific mechanisms by which TERRA contributes to these processes remains unclear. Chu and colleagues investigated the function of TERRA through integrated genomic and proteomic approaches. TERRA localized at telomeric ends at high density, but also associated with nontelomeric DNA, especially the pseudoautosomal regions (PAR) of sex chromosomes, and at introns within genes. TERRA depletion consistently downregulated subtelomeric TERRA-associated target genes and dysregulated expression of internal target genes (either up- or downregulation). Proteomic studies identified TERRA-interacting proteins including the RNA helicase ATRX. TERRA and ATRX co-occupied a number of chromatin sites and had opposing effects on target genes, with TERRA promoting gene expression and ATRX suppressing gene expression. Further, TERRA competed with ATRX for binding to telomeric DNA, and TERRA loss promoted telomere instability. In a related study, Graf, Bonetti, Lockhart, and colleagues found that TERRA preferentially accumulates at R-loops, RNA–DNA hybrids that promote double strand breaks and homology-directed repair (HDR), at short telomeres. Mechanistically, RIF2 recruited RNase H2 and RAT1 to long telomeres to promote degradation of TERRA and R-loops before telomere replication. Short telomeres were unable to associate with RAT1, allowing TERRA to activate the DNA damage response to promote HDR and prevent premature senescence. Taken together, these studies elucidate mechanisms by which TERRA maintains telomere stability and genomic integrity and functions as a transcriptional regulator.

Chu HP, Cifuentes-Rojas C, Kesner B, Aeby E, Lee HG, Wei C, et al. TERRA RNA antagonizes ATRX and protects telomeres. Cell 2017;170:86–101.e16.

Graf M, Bonetti D, Lockhart A, Serhal K, Kellner V, Maicher A, et al. Telomere length determines TERRA and R-loop regulation through the cell cycle. Cell 2017;170:72–85.e14.

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