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
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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.
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Kinetochore inactivation by expression of a repressive mRNA
eLife 6:e27417.
https://doi.org/10.7554/eLife.27417
Further reading
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- 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.
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- Cancer Biology
- Chromosomes and Gene Expression
Telomeres are crucial for cancer progression. Immune signalling in the tumour microenvironment has been shown to be very important in cancer prognosis. However, the mechanisms by which telomeres might affect tumour immune response remain poorly understood. Here, we observed that interleukin-1 signalling is telomere-length dependent in cancer cells. Mechanistically, non-telomeric TRF2 (telomeric repeat binding factor 2) binding at the IL-1-receptor type-1 (IL1R1) promoter was found to be affected by telomere length. Enhanced TRF2 binding at the IL1R1 promoter in cells with short telomeres directly recruited the histone-acetyl-transferase (HAT) p300, and consequent H3K27 acetylation activated IL1R1. This altered NF-kappa B signalling and affected downstream cytokines like IL6, IL8, and TNF. Further, IL1R1 expression was telomere-sensitive in triple-negative breast cancer (TNBC) clinical samples. Infiltration of tumour-associated macrophages (TAM) was also sensitive to the length of tumour cell telomeres and highly correlated with IL1R1 expression. The use of both IL1 Receptor antagonist (IL1RA) and IL1R1 targeting ligands could abrogate M2 macrophage infiltration in TNBC tumour organoids. In summary, using TNBC cancer tissue (>90 patients), tumour-derived organoids, cancer cells, and xenograft tumours with either long or short telomeres, we uncovered a heretofore undeciphered function of telomeres in modulating IL1 signalling and tumour immunity.
