DNA Packaging Reveals that Mutations in Chromatin Remodeling May Cause Cancer
A new discovery from researchers at Huntsman Cancer Institute (HCI) at the University of Utah creates a "180-degree change in focus" for a fundamental understanding of how DNA works
Researchers who study how gene packaging regulates gene activity, believe their findings will influence how genes influence cancer and other diseases.
The discovery, by Bradley R. Cairns, PhD, Senior Director of Basic Science at HCI and a professor in the Department of Oncological Sciences, is reported in this week's online issue of the journal Nature.
Cairns's research is on chromatin remodeling complexes
(CRCs), which are cell protein complexes that behave
like motors to expand or compact portions of DNA
to either express (expand) or silence (compact) genes.
Prior to his research, scientists thought CRC motors
remained at rest until receiving instructions.
However, Cairns and co-author Cedric R. Clapier's
research shows that the CRC motor which is key to
gene packaging and assembly is always turned on,
and requires specific instructions to be turned off.
Cairns: "Many articles in the research literature show that CRCs are mutated in cancer cells. They are intimately involved in regulating gene expression responsible for correctly packaging genes that control growth proliferation and for unpackaging tumor suppressors. This research reveals principles by which CRC mutations could cause cancer."
Chromosomes are made of long DNA strands
wrapped around nodes of protein called nucleosomes.
When DNA is wrapped tightly, genes are turned off.
Disassembly CRCs motors unwind sections of DNA
to activate genes for a given cell process.
Assembly CRCs rewind the DNA chain when
that gene activity is completed.
The unwind-rewind cycle is repeated
continuously throughout a cell's life.
In this study, Cairns and Clapier focused on assembly CRCs.
Cairns: "Before this research, we thought that the motor was off unless a protein coming from another part of the cell turned it on.
"Researchers have been searching for the switch by looking at the CRC motor to see what binds to it. As it turns out, we discovered that the CRC motor already carries on its flank a 'switch' that inhibits its action until a marker sequence, located on the nucleosome, is encountered.
"That marker flips the inhibitor switch and allows the CRC to crank the DNA chain back around the nucleosome, promoting gene packaging and silencing.
"Our results change where future researchers should be looking to understand how CRCs are regulatednot at the CRC motor itself, but at the 'switches' that flank the motor."
Their study also describes a measuring function
on the CRC that checks for the correct distance
between one nucleosome and the next,
telling the motor to switch off at the proper
time, a function needed for gene silencing.
Cairns's lab will now examine this same switching concept in disassembly remodelers. Cairns added: "There are additional remodeler families with alternative functions, like DNA repair. We think this concept will apply to them as well."
This research was supported by funding from the National Institutes of Health (GM60415 and CA042014) and from the Howard Hughes Medical Institute.
The mission of Huntsman Cancer Institute (HCI) at The University of Utah is to understand cancer from its beginnings, to use that knowledge in the creation and improvement of cancer treatments, to relieve the suffering of cancer patients, and to provide education about cancer risk, prevention, and care. HCI is a National Cancer Institute-designated cancer center, which means that it meets the highest national standards for cancer care and research and receives support for its scientific endeavors. HCI is also a member of the National Comprehensive Cancer Network (NCCN), a not-for-profit alliance of the world's leading cancer centers that is dedicated to improving the quality and effectiveness of care provided to patients with cancer. For more information about HCI, please visit www.huntsmancancer.org.
Original article: http://healthcare.utah.edu/publicaffairs/news/current/11-16-2012_dna_packaging.html