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Replicative Stress Induces Intragenic Transcription of the ASE1 Gene that Negatively Regulates Aset Activity

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...

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Bibliographic Details
Published in:Current biology 2014-05, Vol.24 (10), p.1101-1106
Main Authors: McKnight, Kelly, Liu, Hong, Wang, Yanchang
Format: Article
Language:English
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Summary: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 downregulate gene functions in response to DNA replication stress.
ISSN:0960-9822
DOI:10.1016/j.cub.2014.03.040