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. image Timely resolution of sister chromatid cohesion at telomeres by the poly(ADP‐ribose) polymerase tankyrase 1 is essential for genome integrity, but its timing mechanism is unknown. Here, we describe a K63‐linked ubiquitination cycle that ensures telomeres are resolved in the G2/M window of the cell cycle. In late S/G2, tankyrase 1 is polyubiquitinated with K63‐linked chains by the E3 ligase RNF8. Ubiquitinated TNKS1 is stabilized on telomeres to resolve sister telomere cohesion. In G1, the ABRO1/BRCC36‐containing deubiquitinase BRISC cleaves K63‐linked ubiquitin chains off tankyrase 1. Deubiquitination ensures that sister telomeres are not resolved prematurely during S phase.