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DNA 'packaging' linked with cancer

f normal cells, the entire genome became resistant to enzyme digestion. The UIC scientists were able to induce exactly the same effect after just one edge of a normal cell came into contact with laminin, a component of the extracellular matrix.

"Tests showed that in the presence of laminin, the activity of close to 1,000 genes was affected," Folberg said.

Additional experiments demonstrated that the molecules outside a cell exert their influence not by chemical means but mechanically, manipulating the skeletal framework of the cell and the proteins that envelop DNA. These proteins keep the string of DNA -- really, a stiff wire with component nucleotides -- tightly compressed; if the proteins are removed, the genes spring out like a jack-in-the-box.

When the researchers disassembled a cell's skeletal elements -- microtubules, actin and intermediate filaments -- not only did the cell's shape change, but its DNA took on new contours. Segments of DNA became buried inside the wad of genetic material, inaccessible to enzyme digestion.

"Medical research has for decades focused on finding the underlying genetic abnormalities that cause disease, but this work demonstrates that genes themselves are controlled by components outside the nucleus and these, in turn, are regulated by the cell's microenvironment," Maniotis said.

The discovery that normal, benign and malignant tissues respond differently to enzyme digestion could lead to a new diagnostic tool for distinguishing different types of tumors.

The researchers also believe that their findings suggest new therapeutic strategies for combating cancer.

"Many current forms of chemotherapy target DNA directly and are associated with significant side effects," Folberg said. "We're developing methods of manipulating the genome that may be non-toxic and still highly effective."

Other researchers involved in the study were Klara Valyi-Nagy, John Karavitis, Jonas Mos
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Contact: Sharon Butler
sbutler@uic.edu
312-355-2522
University of Illinois at Chicago
22-Mar-2005


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