Interphase Microtubules Safeguard Mitotic Progression by Suppressing an Aurora B-Dependent Arrest Induced by DNA Replication Stress

• Main Authors: Guillaume Laflamme, Shannon Sim, Allen Leary, Mirela Pascariu, Jackie Vogel, Damien D’Amours
• Format: Article
• Language: English
• Published: Elsevier 2019-03-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S221112471930230X

Summary: The segregation of chromosomes is a critical step during cell division. This process is driven by the elongation of spindle microtubules and is tightly regulated by checkpoint mechanisms. It is unknown whether microtubules affect checkpoint responses as passive contributors or active regulators of the process. We show here that interphase microtubules are essential to temporally restrict the effects of DNA replication stress to S phase in Saccharomyces cerevisiae. Tubulin mutants hypersensitive to DNA damage experience a strong but delayed mitotic checkpoint arrest after exposure to genotoxic stress in S phase. This untimely arrest is dependent on the Aurora B kinase but, surprisingly, not on the DNA damage checkpoint. Impaired microtubule-kinetochore interaction is the apparent cause for this unusual phenotype. Collectively, our results reveal that core components of microtubules potentiate the detection of DNA lesions created in S phase, thereby suppressing untimely activation of mitotic checkpoints after DNA replication stress. : DNA replication stress is detected in S phase by a dedicated checkpoint machinery that ensures cells do not enter mitosis with damaged chromosomes. Laflamme et al. found that microtubules limit the effects of replication stress to S phase by modulating the levels of tension at sister kinetochores of replicated chromatids. Keywords: microtubules, Aurora B kinase, replication stress, DNA damage, kinetochore, mitosis, checkpoint