The Aurora-B-dependent NoCut checkpoint prevents damage of anaphase bridges after DNA replication stress

Abstract

Anaphase chromatin bridges can lead to chromosome breakage if not properly resolved before completion of cytokinesis. The NoCut checkpoint, which depends on Aurora B at the spindle midzone, delays abscission in response to chromosome segregation defects in yeast and animal cells. How chromatin bridges are detected, and whether abscission inhibition prevents their damage, remain key unresolved questions. We find that bridges induced by DNA replication stress and by condensation or decatenation defects, but not dicentric chromosomes, delay abscission in a NoCut-dependent manner. Decatenation and condensation defects lead to spindle stabilization during cytokinesis, allowing bridge detection by Aurora B. NoCut does not prevent DNA damage following condensin or topoisomerase II inactivation; however, it protects anaphase bridges and promotes cellular viability after replication stress. Therefore, the molecular origin of chromatin bridges is critical for activation of NoCut, which plays a key role in the maintenance of genome stability after replicative stress.

We thank S. Oliferenko and N. Brownlow for suggestions and critical reading of the manuscript; Y. Barral and D. Pellman for helpful discussions; G. Filion for help with statistical analysis; T. Sanmartin for technical support; the CRG Advanced Light Microscopy Unit; and Y. Schwab (EMBL, Heidelberg), C. López-Iglesias and Y. Muela-Castro (CCIT University of Barcelona) for assistance with electron microscopy. This research was supported by `La Caixa' fellowships to N.A., G.N. and M.Maier, and grants from the Spanish Ministry of Economy and Competitivity (BFU2011-30185 and CDS2009-00016 to M.-I.G.; BFU2015-71308 and BFU2013-50245-EXP to J.T.-R.; and BFU2009-08213 and BFU2012-37162 to M.Mendoza), and from the European Research Council (ERC Starting Grant 260965 to M.Mendoza). We acknowledge support from the Spanish Ministry of Economy and Competitiveness, `Centro de Excelencia Severo Ochoa 2013-2017', SEV-2012-0208.