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Nucleotides: saviors of the cell

Cytochrome c's ATP-binding sites (red and green) overlap with its Apaf1-binding sites (red). TANG/ELSEVIER

Nucleotides are the building blocks of DNA and the cell's energy currency. Now, a report by Dhyan Chandra, Dean Tang (University of Texas, Smithville, TX), and colleagues reveals that these multifunctional molecules are also bodyguards, protecting healthy cells from apoptosis.

The apoptotic cascade unfolds when failing mitochondria leak cytochrome c (cyt c), which then binds to and oligomerizes the caspase activator called Apaf1. Previous experiments showed that low concentrations of nucleotides, in the form of ATP or dATP, were needed for cyt c to bind to Apaf1.

The new results show that higher concentrations of ATP prevent apoptosis. At these higher levels, which match those found in healthy cells, the nucleotides bound up cyt c, thus preventing it from attaching to its Apaf1 partner.

The inhibition was overcome by artificially increasing cyt c levels or decreasing nucleotide concentrations. In healthy cells, sufficient nucleotide levels probably prevent small mitochondrial leaks from triggering death by sequestering the cyt c. Only with persistent cell death signals or unusually low nucleotide levels would cyt c overcome the nucleotide brake.

Low nucleotide levels, the group also shows, are induced by apoptotic signals and anticancer drugs such as etoposide. ATP production probably drops as a result of mitochondrial injury, but what causes the levels of the other nucleotides to drop is unclear as yet.

Reference:

Chandra, D., et al. 2006. Cell. 125:1333–1346.[CrossRef][Medline]

Ruth Williams

ruth.williams{at}rockefeller.edu

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This Article Full Text (PDF, 1373K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Williams, R. Search for Related Content PubMed Articles by Williams, R. Social Bookmarking                            What's this?