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Cell. 2017 Jun 29;170(1):86-101.e16. doi: 10.1016/j.cell.2017.06.017.

TERRA RNA Antagonizes ATRX and Protects Telomeres.

Author information

1
Howard Hughes Medical Institute, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
2
Massachusetts General Hospital Cancer Center, Charlestown, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
3
Howard Hughes Medical Institute, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA. Electronic address: lee@molbio.mgh.harvard.edu.

Abstract

Through an integration of genomic and proteomic approaches to advance understanding of long noncoding RNAs, we investigate the function of the telomeric transcript, TERRA. By identifying thousands of TERRA target sites in the mouse genome, we demonstrate that TERRA can bind both in cis to telomeres and in trans to genic targets. We then define a large network of interacting proteins, including epigenetic factors, telomeric proteins, and the RNA helicase, ATRX. TERRA and ATRX share hundreds of target genes and are functionally antagonistic at these loci: whereas TERRA activates, ATRX represses gene expression. At telomeres, TERRA competes with telomeric DNA for ATRX binding, suppresses ATRX localization, and ensures telomeric stability. Depleting TERRA increases telomerase activity and induces telomeric pathologies, including formation of telomere-induced DNA damage foci and loss or duplication of telomeric sequences. We conclude that TERRA functions as an epigenomic modulator in trans and as an essential regulator of telomeres in cis.

PMID:
28666128
PMCID:
PMC5552367
DOI:
10.1016/j.cell.2017.06.017
[Indexed for MEDLINE]
Free PMC Article

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