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January 21, 2005

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A ‘death patch’ that dooms cells
Shortly after moving to Rockefeller in May 2003, David Allis and his colleagues at the University of Virginia published findings in the journal Cell suggesting that specific chemical “flags” on the protein tails of histones — the spools around which DNA helixes are wound — could induce programmed cell death in mammalian cells.
It was an exciting find, but mammalian cells have thousands of histones, and Allis wanted to determine which specific chemical flags are involved in triggering cell death. So he turned to a simpler organism with just one histone: yeast.
Sung Hee Ahn, a graduate student in Allis’s Laboratory of Chromatin Biology and Epigenetics, took yeast cells from which specific histone tails had been removed, and treated them with hydrogen peroxide, a chemical that triggers the cell death pathway. She found that only the cells lacking the H2B tail survived — indicating the culprit was somewhere on H2B.
Ahn then showed that chemical changes to a specific component of H2B, called serine 10, was implicated: hydrogen peroxide had no effect on the cell when serine 10 was substituted with a different amino acid that does not bind to a phosphate chemical group in the way that serine 10 does (a process called phosphorylation). Ahn also replaced serine 10 with glutamic acid, a molecule that mimics phosphorylated serine 10. According to Allis, the cells looked like they wished they were dead.
“The cells with glutamic acid looked bad before they were exposed to hydrogen peroxide, and looked worse after the treatment,”  says Allis, the university’s Joy and Jack Fishman Professor.
When Ahn and Allis looked closely at the amino acid sequence of H2B, they identified a stretch of amino acids on either side of serine 10 that Allis nicknamed the “death patch.” When this 12-amino acid long peptide was transferred to other histones, those cells also underwent apoptosis, confirming that this section of H2B is critical to the cell death pathway. The results were published in Cell on January 14.
Although more research is needed, Allis believes that these findings may lead the way to new strategies for “de-silencing” genes that are inappropriately shut down in diseases such as cancer, when cells do not die at the time they are supposed to.



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