title: SIRT6 interacts with TRF2 and promotes its degradation in response to DNA damage.
abstract: Telomere repeat binding factor 2 (TRF2) has been increasingly recognized to be involved in telomere maintenance and DNA damage response. Here, we show that TRF2 directly binds SIRT6 in a DNA independent manner and that this interaction is increased upon replication stress. Knockdown of SIRT6 up-regulates TRF2 protein levels and counteracts its down-regulation during DNA damage response, leading to cell survival. Moreover, we report that SIRT6 deactetylates in vivo the TRFH domain of TRF2, which in turn, is ubiquitylated in vivo activating the ubiquitin-dependent proteolysis. Notably, overexpression of the TRF2cT mutant failed to be stabilized by SIRT6 depletion, demonstrating that the TRFH domain is required for its post-transcriptional modification. Finally, we report an inverse correlation between SIRT6 and TRF2 protein expression levels in a cohort of colon rectal cancer patients. Taken together our findings describe TRF2 as a novel SIRT6 substrate and demonstrate that acetylation of TRF2 plays a crucial role in the regulation of TRF2 protein stability, thus providing a new route for modulating its expression level during oncogenesis and damage response.
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Rizzo
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Iachettini
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Salvati
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Zizza
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Maresca
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: D'Angelo
authors.affiliation: Université Côte d'Azur, INSERM U1081 CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Benarroch-Popivker
authors.affiliation: Department of Pharmacy, PhD Program in Drug Discovery and Development, University of Salerno, Via Giovanni Paolo II 132, Fisciano (SA) 84084, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Capolupo
authors.affiliation: Department of Pharmacy, PhD Program in Drug Discovery and Development, University of Salerno, Via Giovanni Paolo II 132, Fisciano (SA) 84084, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Del Gaudio
authors.affiliation: DiSTABiF, Seconda Università di Napoli, Via Vivaldi 43, Caserta 81100, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.affiliation: DiSTABiF, Seconda Università di Napoli, Via Vivaldi 43, Caserta 81100, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Di Maro
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Montesano 49, Naples 80131, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Merlino
authors.affiliation: Department of Pharmacy, University of Naples Federico II, Via Montesano 49, Naples 80131, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
authors.forename: Carla Azzurra
authors.initials: CA
authors.lastname: Amoreo
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Biostatistics Unit, Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Université Côte d'Azur, INSERM U1081 CNRS UMR7284, Institute for Research on Cancer and Aging, Nice (IRCAN), Faculty of Medicine, France.|Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, Via Elio Chianesi 53, Rome 00144, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
mesh_terms: D000107:Acetylation; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D007150:Immunohistochemistry; D008958:Models, Molecular; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D059748:Proteolysis / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D037761:Sirtuins / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D035341:Telomeric Repeat Binding Protein 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011993:Recombinant Fusion Proteins; D035341:Telomeric Repeat Binding Protein 2; D011065:Poly(ADP-ribose) Polymerases; C516592:SIRT6 protein, human; D037761:Sirtuins; D002166:Camptothecin