Journal
RNA
Volume 24, Issue 8, Pages 1018-1027Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1261/rna.065516.117
Keywords
CRISPR; tRNA-derived fragment; oxidative stress ribonuclease inhibitor; RNA processing
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Funding
- National Science Foundation Graduate Research Fellowship
- Advanced Opportunity/Graduate Research Scholar Fellowship
- Molecular Biosciences Training grant (National Institutes of Health) [T32 GM007215]
- National Institutes of Health [R01 CA073808, P30 CA014520]
- University of Wisconsin-Madison Department of Biochemistry Endowment
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Angiogenin (ANG) is a secretory ribonuclease that promotes the proliferation of endothelial cells, leading to angiogenesis. This function relies on its ribonucleolytic activity, which is low for simple RNA substrates. Upon entry into the cytosol, ANG is sequestered by the ribonuclease inhibitor protein (RNH1). We find that ANG is a potent cytotoxin for RNH1-knockout HeLa cells, belying its inefficiency as a nonspecific catalyst. The toxicity does, however, rely on the ribonucleolytic activity of ANG and a cytosolic localization, which lead to the accumulation of particular tRNA fragments (tRFs), such as tRF-5 Gly-GCC. These up-regulated tRFs are highly cytotoxic at physiological concentrations. Although ANG is well-known for its promotion of cell growth, our results reveal that ANG can also cause cell death.
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