Navigation Links
Mechanism of mutant histone protein in childhood brain cancer revealed
Date:4/1/2013

Most cancer treatments are blunt. In an attempt to eradicate tumors, oncologists often turn to radiation or chemotherapy, which can damage healthy tissue along with the cancerous growths. New research from C. David Allis' laboratory at Rockefeller University may bring scientists closer to designing cancer therapeutics that can target tumors with pinpoint accuracy.

Their findings, published last week in Science Express, follow a recent series of discoveries by several international genome sequencing consortiums that directly links a mutated histone protein to a rare brain stem cancer in children called DIPG. Collectively, these studies represented the first time scientists had linked a histone mutation to a disease, and piqued the interest of Peter Lewis, a research associate in Allis' Laboratory of Chromatin Biology and Epigenetics, who spearheaded these new studies.

Together with DNA, histones comprise the gene packaging material called chromatin. The mutation occurs on histone H3, and involves the remarkably specific substitution of one amino acid, lysine, for another, methionine, at a key position on the histone's tail, "silencing" the associated gene. Normally, gene silencing arises when an enzyme called a methyltransferase, containing a structural region called the SET domain, attaches a methyl chemical group to the lysine at position 27 in the H3 tail. This highly specific chemical reaction, called methylation, is disrupted by the replacement of the lysine with methionine, which could result in gene mis-regulation.

Lewis and his colleagues looked at human DIPG tumors that contained the lysine-to-methionine substitution and determined that mutated histone H3 comprised anywhere from 3.6 percent to 17.6 percent of total H3 in DIPG samples. They also found a global reduction in the levels of methylation of normal H3 histones when small amounts of the mutant H3 were added to normal human cells.

"I have often said, 'Every amino acid in histones matters,'" says Allis, who is the Joy and Jack Fishman Professor. "These studies underscore just how true that may be."

The researchers went on to demonstrate that the reduction in methylation of normal H3 histones results from interference with activity of a methyltransferase called PRC2 by the mutant histone. Methylation of normal H3 by PRC2 leads to repression of genes involved in cellular growth pathways. Without methylation, genes involved in these pathways likely become activated, promoting the growth of tumors in DIPG. Allis and Lewis received funding from the National Institutes of Health and the Starr Cancer Consortium. Key collaborators in this work included Oren Becher at Duke University Medical Center and Tom Muir at Princeton University and their colleagues.

"Our finding provides us with a useful tool for probing biological processes," says Lewis. "This also tells us how to inhibit enzymes, which could lead to the development of pharmaceuticals that mimic the action of these mutants."

"We now have a model for the promotion of brain stem cancers through aberrant epigenetic silencing through the inhibition of PRC2 by a mutant histone," says Allis. "We have uncovered a potentially useful mechanism to exclusively inhibit individual SET-domain methyltransferases, and conceivably other chromatin-modifying enzymes, implicated in a variety of malignancies."


'/>"/>

Contact: Joseph Bonner
joseph.bonner@rockefeller.edu
212-327-8998
Rockefeller University
Source:Eurekalert

Related biology news :

1. Researchers find novel mechanism regulating replication of insulin-producing beta cells
2. New study identifies unique mechanisms of antibiotic resistance
3. UMass Amherst researchers reveal mechanism of novel biological electron transfer
4. Series of studies first to examine acupunctures mechanisms of action
5. Whole genome sequencing of wild rice reveals the mechanisms underlying oryza genome evolution
6. Antarctic and Arctic insects use different genetic mechanisms to cope with lack of water
7. Epigenetics mechanism may help explain effects of moms nutrition on her childrens health
8. IRB Barcelona researchers discover mechanism that regulates steroid hormone production in Drosophila
9. Researchers explain a key developmental mechanism for the first time in plants
10. Novel storage mechanism allows command, control of memory
11. Mechanisms regulating inflammation associated with type 2 diabetes, cancer identified
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/28/2017)... , February 28, 2017 News solutions ... ... Amsterdam from 14 to 16 March, Materna will ... and show how seamless travel is a real benefit for passengers. ... added biometrics to their passenger touch point solutions to take passengers ...
(Date:2/26/2017)... 25, 2017  Securus Technologies, a leading provider ... public safety, investigation, corrections and monitoring, announces the ... "Too often, too many offenders return ... jails are trying to tackle this ongoing problem ... and family members. While significant steps are underway, Securus ...
(Date:2/21/2017)... PORTLAND, Ore. , Feb. 22, 2017  IBM ... Companies (Avamere Health Services, Infinity Rehab, Signature Hospice, Home ... that will apply the power of IBM cognitive computing ... health centers. By analyzing data streaming from sensors in ... physical and environmental conditions, and obtain deeper learnings into ...
Breaking Biology News(10 mins):
(Date:3/24/2017)... Sinovac Biotech Ltd. ("Sinovac" or the "Company") (NASDAQ: SVA), ... , today announced that its board of directors has amended its ... from March 27, 2017 to March 27, 2018. The amendment was not ... Biotech Ltd. ... Sinovac Biotech Ltd. is a China -based ...
(Date:3/23/2017)... ... 23, 2017 , ... AxioMed president, Jake Lubinski, describes the ... when deformed, which is identical to how the human discs work to distribute ... return to its natural state along a hysteresis curve, exactly like a healthy ...
(Date:3/23/2017)... 2017  SeraCare Life Sciences, Inc., a manufacturer ... diagnostics manufacturers and clinical laboratories, is announcing ... Inherited Cancer reference material for ... sequencing (NGS). The Seraseqâ„¢ Inherited Cancer DNA Mix ... industry experts to validate the ability of ...
(Date:3/23/2017)... , March 23, 2017 Kineta, ... development of novel therapies in immuno-oncology, today announced ... lead" small molecule compounds that activate interferon response ... pathways and demonstrate immune-mediated tumor regression in a ... the study who demonstrated complete tumor regression to ...
Breaking Biology Technology: