Replicative stress induces intragenic transcription of the ASE1 gene that negatively regulates Ase1 activity

Article, Other literature type English OPEN
McKnight, Kelly ; Liu, Hong ; Wang, Yanchang (2014)
  • Publisher: Elsevier BV
  • Journal: Current Biology, volume 24, issue 10, pages 1,101-1,106 (issn: 0960-9822)
  • Related identifiers: doi: 10.1016/j.cub.2014.03.040
  • Subject: Agricultural and Biological Sciences(all) | Biochemistry, Genetics and Molecular Biology(all) | Article

Intragenic transcripts initiate within the coding region of a gene, thereby producing shorter mRNAs and proteins. Although intragenic transcripts are widely expressed [1], their role in the functional regulation of genes remains largely unknown. In budding yeast, DNA replication stress activates the S-phase checkpoint that stabilizes replication forks and arrests cells in S-phase with a short spindle [2-4]. When yeast cells were treated with hydroxyurea (HU) to block DNA synthesis and induce replication stress, we found that Ase1, a conserved spindle midzone protein [5], appeared as two short protein isoforms in addition to the full-length protein. We further demonstrated that the short isoforms result from intragenic transcription of ASE1, which depends on the S-phase checkpoint. Blocking generation of the short isoforms leads to a destabilized S-phase spindle, characterized by increased spindle dynamics and frequent spindle collapse. Because the short Ase1 isoforms localize at the spindle in HU-treated cells and overexpression of the short Ase1 isoforms impairs the spindle midzone localization of full-length Ase1, it is likely that the presence of short Ase1 isoforms stabilizes the spindle by antagonizing full-length Ase1. Together, our results reveal intragenic transcription as a unique mechanism to down-regulate gene functions in response to DNA replication stress.
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