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A discovery concerning how genes are switched on and off through a process called gene packaging amounts to a “180-degree change in focus” for researchers who study the genes that cause cancer and other diseases. The discovery, by Bradley R. Cairns, PhD, Senior Director of Basic Science at Huntsman Cancer Institute and a professor in the Department of Oncological Sciences, was published in the December 13, 2012, issue of the journal Nature.
Cairns’ research focuses on chromatin remodeling complexes (CRCs), which are groups of proteins that behave like motors inside the cell’s nucleus, expanding or compacting different portions of DNA to either express or silence genes. Before, scientists thought that the motor within CRCs waits at rest until it receives instructions. Cairns and co-author Cedric R. Clapier, PhD, a Cairns Lab member, show that the motor within a key CRC responsible for gene packaging and assembly is already turned on, and instead needs specific instructions to turn it off.
“Research has shown that CRCs are often 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,” says Cairns. “This study reveals principles by which CRC mutations could cause cancer.”
Chromosomes are made of long DNA strands coiled around disks of proteins called nucleosomes. Assembly CRCs wind the DNA coils tight and pack the nucleosomes close together in chromosome regions that harbor silent genes. Disassembly CRCs unwind sections of DNA chains, removing nucleosomes and promoting gene activity at the proper time to control all cell processes, including those important for metabolism and growth. For many genes, the unwind-rewind cycle is repeated continuously throughout a cell’s life. Defects in either assembly CRCs or disassembly CRCs can silence or activate genes incorrectly. Cancer and other diseases can result. In this study, Cairns and Clapier focused on assembly CRCs.
“We discovered the CRC motor carries on its flank a ‘switch’ that inhibits its action until a marker sequence, located on the nucleosome, is encountered. The marker flips the inhibitor switch and allows the CRC to turn on, and crank the DNA chain back around the nucleosome, promoting gene packaging and silencing,” Cairns says. “In fact, we found two separate switches, controlled by two separate markers. Our results change where future researchers should be looking to understand how CRCs are regulated—not at the CRC motor itself, but at the ‘switches’ that flank the motor.”
The change in focus brings researchers one step closer to finding out why certain cancers happen and how to stop them. The Cairns Lab will now examine this same switching concept in disassembly remodelers. “There are additional remodeler families with alternative functions, like DNA repair,” says Cairns. “We think this concept will apply to them as well.”
Used with permission from the Howard Hughes Medical Institute, Copyright (2002). All rights reserved.