title: Functional characterization of the TERRA transcriptome at damaged telomeres.
abstract: Telomere deprotection occurs during tumorigenesis and aging upon telomere shortening or loss of the telomeric shelterin component TRF2. Deprotected telomeres undergo changes in chromatin structure and elicit a DNA damage response (DDR) that leads to cellular senescence. The telomeric long noncoding RNA TERRA has been implicated in modulating the structure and processing of deprotected telomeres. Here, we characterize the human TERRA transcriptome at normal and TRF2-depleted telomeres and demonstrate that TERRA upregulation is occurring upon depletion of TRF2 at all transcribed telomeres. TRF2 represses TERRA transcription through its homodimerization domain, which was previously shown to induce chromatin compaction and to prevent the early steps of DDR activation. We show that TERRA associates with SUV39H1 H3K9 histone methyltransferase, which promotes accumulation of H3K9me3 at damaged telomeres and end-to-end fusions. Altogether our data elucidate the TERRA landscape and defines critical roles for this RNA in the telomeric DNA damage response.
authors.affiliation: 1] Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland [2] Swiss Institute for Experimental Cancer Research (ISREC) at EPFL, Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Porro
authors.affiliation: 1] Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland [2] Swiss Institute for Experimental Cancer Research (ISREC) at EPFL, Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Sascha
authors.initials: S
authors.lastname: Feuerhahn
authors.affiliation: 1] Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland [2] Bioinformatics and Biostatistics Core Facility, EPFL and Swiss Institute of Bioinformatics, Station 15, CH-1015 Lausanne, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Delafontaine
authors.affiliation: The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Harold
authors.initials: H
authors.lastname: Riethman
authors.affiliation: 1] Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland [2] Bioinformatics and Biostatistics Core Facility, EPFL and Swiss Institute of Bioinformatics, Station 15, CH-1015 Lausanne, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Rougemont
authors.affiliation: 1] Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland [2] Swiss Institute for Experimental Cancer Research (ISREC) at EPFL, Station 19, CH-1015 Lausanne, Switzerland.
authors.forename: Joachim
authors.initials: J
authors.lastname: Lingner
mesh_terms: D004249:DNA Damage; D020869:Gene Expression Profiling; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008780:Methyltransferases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D062085:RNA, Long Noncoding / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism*; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D062085:RNA, Long Noncoding; D012097:Repressor Proteins; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; C407843:SUV39H1 protein, human; D008780:Methyltransferases; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5