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

Cell Rep. 2019 Mar 12;26(11):2875-2889.e3. doi: 10.1016/j.celrep.2019.02.051.

Abstract

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.

Keywords: Aurora B kinase; DNA damage; checkpoint; kinetochore; microtubules; mitosis; replication stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase B / genetics*
  • Aurora Kinase B / metabolism
  • DNA Damage
  • DNA Replication*
  • Interphase*
  • Kinetochores / metabolism
  • Microtubules / metabolism*
  • Mitosis*
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism

Substances

  • Saccharomyces cerevisiae Proteins
  • Tub2 protein, S cerevisiae
  • Aurora Kinase B