title: The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection.
abstract: The mammalian shelterin component TPP1 has essential roles in telomere maintenance and, together with POT1, is required for the repression of DNA damage signaling at telomeres. Here we show that in Mus musculus, the E3 ubiquitin ligase Rnf8 localizes to uncapped telomeres and promotes the accumulation of DNA damage proteins 53Bp1 and γ-H2ax. In the absence of Rnf8, Tpp1 is unstable, resulting in telomere shortening and chromosome fusions through the alternative nonhomologous end-joining (A-NHEJ) repair pathway. The Rnf8 RING-finger domain is essential for Tpp1 stability and retention at telomeres. Rnf8 physically interacts with Tpp1 to generate Ubc13-dependent Lys63 polyubiquitin chains that stabilize Tpp1 at telomeres. The conserved Tpp1 residue Lys233 is important for Rnf8-mediated Tpp1 ubiquitylation and localization to telomeres. Thus, Tpp1 is a newly identified substrate for Rnf8, indicating a previously unrecognized role for Rnf8 in telomere end protection.
authors.affiliation: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Rai
authors.forename: Ju-Mei
authors.initials: JM
authors.lastname: Li
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.forename: Gabriel Tsz-Mei
authors.initials: GT
authors.lastname: Lok
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.forename: Michael S-Y
authors.initials: MS
authors.lastname: Huen
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
authors.forename: Sandy
authors.initials: S
authors.lastname: Chang
mesh_terms: D000818:Animals; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051379:Mice; D025941:Protein Interaction Mapping; D055550:Protein Stability; D016615:Telomere / Q000737:chemistry*; D034501:Telomere-Binding Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D054875:Ubiquitination
chemical_list: C544060:Acd protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; D034501:Telomere-Binding Proteins; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; C475961:gamma-H2AX protein, mouse; C549817:Rnf8 protein, mouse; D044767:Ubiquitin-Protein Ligases
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