The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection
Copyright policy )The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection
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.
- The University of Texas MD Anderson Cancer Center United States
- Yale University United States
- University of Hong Kong China (People's Republic of)
- University of Hong Kong (香港大學) China (People's Republic of)
- The University of Texas Health Science Center at Houston United States
570, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - chemistry - metabolism, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins - metabolism, Ubiquitin-Protein Ligases, Telomere-Binding Proteins, Chromosomes, Mammalian - metabolism, Chromosomes, Histones, Mice, Protein Interaction Mapping, Serine Proteases - chemistry - metabolism, Ubiquitin-Protein Ligases - analysis - chemistry - physiology, Animals, Aminopeptidases - chemistry - metabolism, Protein Stability, Telomere - chemistry, Ubiquitination, Telomere, Non-Histone - metabolism, Chromosomes, Mammalian, Chromosomal Proteins, DNA-Binding Proteins, Chromosomal Proteins, Non-Histone - metabolism, Proteasome Endopeptidase Complex - metabolism, Histones - metabolism, Tumor Suppressor p53-Binding Protein 1, Mammalian - metabolism, DNA Damage
570, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases - chemistry - metabolism, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins - metabolism, Ubiquitin-Protein Ligases, Telomere-Binding Proteins, Chromosomes, Mammalian - metabolism, Chromosomes, Histones, Mice, Protein Interaction Mapping, Serine Proteases - chemistry - metabolism, Ubiquitin-Protein Ligases - analysis - chemistry - physiology, Animals, Aminopeptidases - chemistry - metabolism, Protein Stability, Telomere - chemistry, Ubiquitination, Telomere, Non-Histone - metabolism, Chromosomes, Mammalian, Chromosomal Proteins, DNA-Binding Proteins, Chromosomal Proteins, Non-Histone - metabolism, Proteasome Endopeptidase Complex - metabolism, Histones - metabolism, Tumor Suppressor p53-Binding Protein 1, Mammalian - metabolism, DNA Damage
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