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'K-to-M' histone mutations: How repressing the repressors may drive tissue-specific cancers
Date:8/29/2014

Kansas City, MO. - In a cell's nucleus, chromosomal DNA is tightly bound to structural proteins known as histones, an amalgam biologists call chromatin. Until about two decades ago, histones were regarded as a nuclear "sidekick," the mere packing material around which the glamorous DNA strands were wrapped. Recently, however, biologists have developed a greater appreciation for how DNA/histone interactions govern gene expression.

In 2012, investigators from multiple research institutions studying the sequence of the genome from cancer patients rocked the "chromatin world" when they independently reported that mutations in the gene that encodes histone H3.3 occurred in aggressive pediatric brain tumors. This finding was stunning, as researchers had never before associated histone mutations with any disease, much less a deadly tumor. What followed was a race by cancer researchers worldwide to discover how histone mutations might promote tumorigenesis.

Now a paper from a laboratory at the Stowers Institute of Medical Research reports the first animal model created to assess the molecular effects of two different histone H3.3 mutations in the fruit fly Drosophila. The study from a team led by Investigator Ali Shilatifard, Ph.D. published in the August 29, 2014 issue of Science, strongly suggests that these mutations actually could drive cancer and identifies interacting partners and pathways that could be targeted for the treatment of cancer.

Molecular biologists categorize these mutations as "K-to-M", because a normal lysine residue (symbolized by K) in the protein is replaced by methionine (M) through mutations in the DNA sequence. In pediatric tumors, K-to-M mutations occurred at lysine residue 27 (K27) of histone H3.3. Researchers suggested that the presence of even a small population of these damaged proteins in the nucleus muffled a large repressor complex called PRC2. Normally, PRC2 acts as an enzyme to decorate h
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Contact: Kim Bland, Ph.D.
ksb@stowers.org
816-926-4015
Stowers Institute for Medical Research
Source:Eurekalert  

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