title: Cell cycle-regulated ubiquitination of tankyrase 1 by RNF8 and ABRO1/BRCC36 controls the timing of sister telomere resolution.
abstract: Timely resolution of sister chromatid cohesion in G2/M is essential for genome integrity. Resolution at telomeres requires the poly(ADP-ribose) polymerase tankyrase 1, but the mechanism that times its action is unknown. Here, we show that tankyrase 1 activity at telomeres is controlled by a ubiquitination/deubiquitination cycle depending on opposing ubiquitin ligase and deubiquitinase activities. In late S/G2 phase, the DNA damage-responsive E3 ligase RNF8 conjugates K63-linked ubiquitin chains to tankyrase 1, while in G1 phase such ubiquitin chains are removed by BRISC, an ABRO1/BRCC36-containing deubiquitinase complex. We show that K63-linked ubiquitin chains accumulate on tankyrase 1 in late S/G2 to promote its stabilization, association with telomeres, and resolution of cohesion. Timing of this posttranslational modification coincides with the ATM-mediated DNA damage response that occurs on functional telomeres following replication in G2. Removal of ubiquitin chains is controlled by ABRO1/BRCC36 and occurs as cells exit mitosis and enter G1, ensuring that telomere cohesion is not resolved prematurely in S phase. Our studies suggest that a cell cycle-regulated posttranslational mechanism couples resolution of telomere cohesion with completion of telomere replication to ensure genome integrity.
authors.affiliation: Kimmel Center for Biology and Medicine at the Skirball Institute, Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Ekta
authors.initials: E
authors.lastname: Tripathi
authors.affiliation: Kimmel Center for Biology and Medicine at the Skirball Institute, Department of Pathology, New York University School of Medicine, New York, NY, USA susan.smith@med.nyu.edu.
authors.forename: Susan
authors.identifier: 0000-0002-8213-5915
authors.initials: S
authors.lastname: Smith
mesh_terms: D002453:Cell Cycle; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000072017:Deubiquitinating Enzymes; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D034521:Nuclear Matrix-Associated Proteins / Q000378:metabolism*; D038501:Tankyrases / Q000378:metabolism*; D016615:Telomere / Q000201:enzymology / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D000072017:Deubiquitinating Enzymes; D008565:Membrane Proteins; D034521:Nuclear Matrix-Associated Proteins; D038501:Tankyrases; D044767:Ubiquitin-Protein Ligases; D064570:Ubiquitin-Specific Proteases; C577338:ABRAXAS2 protein, human; C486521:RNF8 protein, human; C418109:TNKS protein, human; C518017:BRCC3 protein, human
keywords: RNF8; cohesion; poly(ADP‐ribose); tankyrase; telomere