Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 43, Pages 26773-26783Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2002360117
Keywords
eIF4E; RNMT; methyl-7-guanosine cap; RNA capping
Categories
Funding
- NIH [R01 CA80728, R01 CA98571]
- Canadian Institutes of Health Research [PJT159785]
- Leukemia & Lymphoma Society USA Translational Research Program (LLS USA TRP) [R6513-20]
- Canada Research Chair in Molecular Biology of the Cell Nucleus
- LLS USA TRP [R6510-19]
- Kellen Foundation
- Department of Medicine Postdoctoral Scholar Award
- MRC [MR/K024213/1] Funding Source: UKRI
Ask authors/readers for more resources
Methyl-7-guanosine (m(7)G) capping of coding and some noncoding RNAs is critical for their maturation and subsequent activity. Here, we discovered that eukaryotic translation initiation factor 4E (eIF4E), itself a cap-binding protein, drives the expression of the capping machinery and increased capping efficiency of similar to 100 coding and noncoding RNAs. To quantify this, we developed enzymatic (cap quantification; CapQ) and quantitative cap immunoprecipitation (CapIP) methods. The CapQ method has the further advantage that it captures information about capping status independent of the type of 5' cap, i.e., it is not restricted to informing on m(7)G caps. These methodological advances led to unanticipated revelations: 1) Many RNA populations are inefficiently capped at steady state (similar to 30 to 50%), and eIF4E overexpression increased this to similar to 60 to 100%, depending on the RNA; 2) eIF4E physically associates with noncoding RNAs in the nucleus; and 3) approximately half of eIF4E-capping targets identified are noncoding RNAs. eIF4E's association with noncoding RNAs strongly positions it to act beyond translation. Coding and noncoding capping targets have activities that influence survival, cell morphology, and cell-to-cell interaction. Given that RNA export and translation machineries typically utilize capped RNA substrates, capping regulation provides means to titrate the protein-coding capacity of the transcriptome and, for noncoding RNAs, to regulate their activities. We also discovered a cap sensitivity element (CapSE) which conferred eIF4E-dependent capping sensitivity. Finally, we observed elevated capping for specific RNAs in high-eIF4E leukemia specimens, supporting a role for cap dysregulation in malignancy. In all, levels of capping RNAs can be regulated by eIF4E.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available