Aug. 30, 2002 PHILADELPHIA - When cells divide in two, they must carefully manage the process by which their DNA is replicated and then apportioned to the daughter cells. In one critical step along the way, the replicated DNA strands - or sisters - are held together for a period by a temporary scaffold of bridging proteins. When the timing is right, the proteins unzip, allowing the DNA sisters to separate. Errors in this or other steps in cell division can lead to cell death, faulty development, or cancer, which is largely defined as misregulated cell division.
Scientists have had a number of questions about these important bridging proteins, called cohesins. For example, how and where do the proteins attach themselves to the DNA? To protect genes from inappropriate activation, DNA is tightly wrapped around small proteins called histones and then further coiled into a higher structure called chromatin that serves as an effective accessibility barrier to the genes.
In a new study in the August 29 issue of Nature, researchers at The Wistar Institute identify a cohesin-containing protein complex that reshapes chromatin to allow cohesins to bind to DNA. In doing so, they also identified the locations on the human genome where the cohesins bind. Somewhat to their surprise, the binding sites were found to be a repetitive DNA sequence found throughout the human genome for which no previous role had ever been identified. These bits of DNA, known as Alu sequences, are liberally represented along those vast stretches of the human genome not known to directly control genetic activity, sometimes referred to as junk DNA.
"One thing that interested us is that there are 500 thousand to 1 million Alu repeats across the human genome," says Ramin Shiekhattar, Ph.D., an associate professor at The Wistar Institute and senior author on the Nature study. "These sequences are very common. And this makes sense if one of their roles is to bind to the bridging proteins, the cohesins, to keep the replicated DNA sisters together until it is time for them to separate. Multiple bridging sites throughout the DNA would be needed for this system to work. They couldn't be unique sequences."
In their investigations, Shiekhattar and his coworkers noticed that many, but not all the Alu sequences bound cohesin, and they wondered what rules might govern the process. Additional experiments revealed that if the histone proteins were methylated and acetylated - that is, if a methyl and acetyl molecule were bound to them - then the chromatin structure relaxed to allow access to the DNA. But if the Alu sequence on the DNA was itself methylated, then the cohesin could not bind to the DNA at that site.
Why these modifications might take place at some Alu sites and not others was not clear. But, taken together, the research team's observations are supportive of the existence of what some scientists have termed a "histone code." This recently proposed theory suggests that a system of complex, interdependent modifications to histones is responsible for regulating access to DNA and genes.
"The idea that a kind of code of modifications to the molecular packaging of DNA may govern gene activity is an intriguing one," Shiekhattar says. "If we were to better understand this code, it might provide us with important insights into diseases tied to problems in gene control, including developmental disorders and cancer. These are some of the questions we're looking into now, using this study as a starting point."
The lead author on the Nature study is Mohamed-Ali Hakimi, Ph.D., at The Wistar Institute. The other Wistar-based coauthors are Daniel A. Bochar, Ph.D., Yuanshu Dong, and Orr G. Barak. Wistar professor David W. Speicher, Ph.D., collaborated on the study, as did John A. Schmiesing, Jr., and Kyoko Yokomori at the University of California, Irvine. This research was supported by a grant from National Institutes of Health.
The Wistar Institute is an independent nonprofit biomedical research institution dedicated to discovering the causes and cures for major diseases, including cancer, cardiovascular disease, autoimmune disorders, and infectious diseases. Founded in 1892 as the first institution of its kind in the nation, The Wistar Institute today is a National Cancer Institute-designated Cancer Center - one of only eight focused on basic research. Discoveries at Wistar have led to the development of vaccines for such diseases as rabies and rubella, the identification of genes associated with breast, lung, and prostate cancer, and the development of monoclonal antibodies and other significant research technologies and tools.
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