New compounds give voice to silenced neural DNA

A potential therapy for Friedreich's ataxia, a neurodegenerative disease that is caused by gene activation, is described in the October issue of Nature Chemical Biology.

Frataxin, a protein that protects neurons from cell death caused by free radicals, is 'silenced' in the neurodegenerative disease Friedreich's ataxia. The production of a gene can be regulated by changing the chemical tags attached to nearby histones, or beads that DNA is wrapped around inside the cell. In Friedreich's ataxia, an expansion in the 'noncoding' portion of FXN (the gene encoding frataxin) and modification of the gene's associated histones results in silencing FXN transcription. Gottesfeld and colleagues have identified a class of inhibitors that reverse the silencing in cells in people with Friedreich's ataxia. The inhibitors specifically changed the chemical modifications of the histones around FXN.

These compounds now join the handful of therapeutics that activate specific gene transcription in a human disease.

Patient-specific cancer treatment

Scientists have discovered a way to cause some cancerous cells to self-destruct. These findings, reported in the October issue of Nature Chemical Biology, describe the use of a small molecule to 'wake up' the key enzyme -- caspase-3 -- that causes cell death.

Caspase-3 normally exists as a proenzyme, meaning that further processing is required to make the final, active enzyme. This processing is normally performed by other caspases and serves as a signal that something has gone wrong with a cell; it signals that cell death or 'apoptosis' is desired. Paul Hergenrother and colleagues have now used the synthetic compound PAC-1 to trick procaspase-3 into processing itself, generating caspase-3 and causing cell death. They demonstrated, in a variety of cancer cell types, that cell death is correlated with the amount of procaspase-3 present in the cells, with more procaspase-3 resulting in cell death at lower concentrations of PAC-1, while healthy cells remain unaffected.

The variability of procaspase-3 levels in the cell lines tested means that some patients would be more responsive to this therapy than others. As such, this research potentially offers a novel opportunity for individualized cancer therapy.

Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia

David Herman, Kai Jenssen, Ryan Burnett, Elisabetta Soragni, Susan L Perlman and Joel M Gottesfeld

Published online: 20 August 2006 | doi 10.1038/nchembio815

Abstract | Full text | PDF | Supplementary information

Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy

Karson S Putt, Grace W Chen, Jennifer M Pearson, Joseph S Sandhorst, Martin S Hoagland, Jung-Taek Kwon, Soon-Kyung Hwang, Hua Jin, Mona I Churchwell, Myung-Haing Cho, Daniel R Doerge, William G Helferich and Paul J Hergenrother

Published online: 27 August 2006 | doi 10.1038/nchembio814

Abstract | Full text | PDF | Supplementary information