Kinetochore inactivation by expression of a repressive mRNA
- University of California, Berkeley, United States
- The Francis Crick Institute, United Kingdom
- Li Ka Shing Center, University of California, United States
- University of California, United States
Abstract
Differentiation programs such as meiosis depend on extensive gene regulation to mediate cellular morphogenesis. Meiosis requires transient removal of the outer kinetochore, the complex that connects microtubules to chromosomes. How the meiotic gene expression program temporally restricts kinetochore function is unknown. We discovered that in budding yeast, kinetochore inactivation occurs by reducing the abundance of a limiting subunit, Ndc80. Furthermore, we uncovered an integrated mechanism that acts at the transcriptional and translational level to repress NDC80 expression. Central to this mechanism is the developmentally controlled transcription of an alternate NDC80 mRNA isoform, which itself cannot produce protein due to regulatory upstream ORFs in its extended 5' leader. Instead, transcription of this isoform represses the canonical NDC80 mRNA expression in cis, thereby inhibiting Ndc80 protein synthesis. This model of gene regulation raises the intriguing notion that transcription of an mRNA, despite carrying a canonical coding sequence, can directly cause gene repression.
Data availability
-
High-resolution view of the yeast meiotic program revealed by ribosome profilingPublicly available at the NCBI Gene Expression Omnibus (accession no. GSE34082).
Article and author information
Author details
Folkert Jacobus van Werven
Funding
March of Dimes Foundation (5-FY15-99)
- Elcin Unal
Pew Charitable Trusts (27344)
- Elcin Unal
Glenn Foundation for Medical Research
- Elcin Unal
Francis Crick Institute
- Folkert Jacobus van Werven
National Science Foundation
- Jingxun Chen
Agency for Science, Technology and Research
- Minghao Chia
Damon Runyon Cancer Research Foundation (35-15)
- Elcin Unal
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Chen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,800
- views
-
- 591
- downloads
-
- 77
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Kinetochore inactivation by expression of a repressive mRNA
eLife 6:e27417.
https://doi.org/10.7554/eLife.27417
Further reading
-
- Chromosomes and Gene Expression
A key protein involved in the segregation of meiotic chromosomes is produced 'just in time' by the regulated expression of two mRNA isoforms.
-
- Chromosomes and Gene Expression
- Evolutionary Biology
Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with L1 transcripts and interacts with L1 ORF1p protein, thereby facilitating L1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral L1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of L1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.
