Dr. Benjamin Gold, working with Dr. Carl Nathan, chairman of microbiology and immunology at Weill Cornell Medical College and their colleagues, located a protein called mycobacterial metallothionein (MymT), which acts like a shield to protect the tuberculosis bacterium from the body's natural defenses.

The tuberculosis bacterium lurks within cells called macrophages -- immune system cells that bombard harmful microbes with a soup of chemicals, including nitric oxide. The researchers believe that the newly discovered protein helps the bacterium resist a newly discovered action of nitric oxide, thus allowing the infection to stay strong within the body. The Weill Cornell scientists discovered nitric oxide can liberate copper from proteins within the bacterium, and may also reduce it from a relatively harmless form to lethal form. The new protein, MymT, binds the copper to protect the bacterium from being poisoned by the metal.

All the genetic information in the tuberculosis organism was sequenced in 1998. Yet the gene encoding MymT was overlooked until now because of its very small size and the novel way it encodes the protein. Thus, this study suggests that there may be other genes in bacterial pathogens that contribute to their potential to cause disease, but which have otherwise been overlooked, including relatives of MymT.

The study is published in a recent issue of the journal Nature Chemical Biology.

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Further experiments were done with colleagues in the Peptide Synthesis Service at Rockefeller's Proteomics Resource Center, who constructed a series of peptides that mirrored the section of the H3 tail that flanked the cleavage, but with different modifications to specific amino acids. Duncan found that methylated lysine 27 in the tail of H3 enhanced the cleavage reaction. Acetylation of lysine 18 also seemed to increase the likelihood of cleavage by cathepsin L, while acetylation of lysine 23 significantly decreased this cleavage.

In addition to the finding's implications for understanding gene expression in embryonic stem cell differentiation, the role of acetylation in H3 clipping also raises questions about the effect of a new class of cancer drugs called HDAC inhibitors. HDAC inhibitors block the removal of acetyl groups, which are known gene activators, from histones. As acetyl groups begin to accumulate, genes that have been mistakenly silenced in tumors begin to be reactivated.

"It's now a formal possibility from Beth's work that when you build up acetyl marks you may perturb some of these clips," says Allis, who provided some of the first evidence for histone clipping as a postdoc in 1980. "We are aware now that we should go back and reexamine the patient samples of people who are getting these HDAC inhibitors in clinical trials and see if this is happening."

Cell 135(2): 284-294 (October 17, 2008)

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