title: DNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs.
abstract: The DNA damage response (DDR) is a set of cellular events that follows the generation of DNA damage. Recently, site-specific small non-coding RNAs, also termed DNA damage response RNAs (DDRNAs), have been shown to play a role in DDR signalling and DNA repair. Dysfunctional telomeres activate DDR in ageing, cancer and an increasing number of identified pathological conditions. Here we show that, in mammals, telomere dysfunction induces the transcription of telomeric DDRNAs (tDDRNAs) and their longer precursors from both DNA strands. DDR activation and maintenance at telomeres depend on the biogenesis and functions of tDDRNAs. Their functional inhibition by sequence-specific antisense oligonucleotides allows the unprecedented telomere-specific DDR inactivation in cultured cells and in vivo in mouse tissues. In summary, these results demonstrate that tDDRNAs are induced at dysfunctional telomeres and are necessary for DDR activation and they validate the viability of locus-specific DDR inhibition by targeting DDRNAs.
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rossiello
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Julio
authors.initials: J
authors.lastname: Aguado
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Sepe
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Iannelli
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Quan
authors.initials: Q
authors.lastname: Nguyen
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Cancer Center, MI 48109, Ann Arbor, USA.
authors.forename: Sethuramasundaram
authors.initials: S
authors.lastname: Pitchiaya
authors.affiliation: RIKEN Center for Life Science Technologies, Division of Genomic Technologies, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Piero
authors.identifier: 0000-0001-7202-7243
authors.initials: P
authors.lastname: Carninci
authors.affiliation: IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy.|Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (IGM-CNR), Via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: d'Adda di Fagagna
mesh_terms: D000818:Animals; D004249:DNA Damage; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects / Q000235:genetics; D043244:Ribonuclease III / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D016376:Oligonucleotides, Antisense; D012313:RNA; C513400:Drosha protein, mouse; D043244:Ribonuclease III