SEATTLE - Cancer cells are a mishmash of DNA damage: broken chromosomes, rearranged bases, chromosomes or too short too long. But despite the wealth of observed associations between DNA damage and tumors, scientists are just beginning to understand the genetic accidents that result in tumor progression. Now, a team found that mice with defects in DNA repair are especially prone to tumors.
A crowd of insults can damage DNA, ultraviolet light or certain chemicals to defects in the own ability of DNA to replicate. Cells have two repair options closely related: the shift repair and proofreading, each based on a separate group of enzymes called polymerases. It was ten years ago, scientists linked mutations in mismatch repair genes to a rare cancer called hereditary colon cancer without polyposis. But no other human cancers have been linked to DNA repair replication defects.
Bradley Preston, a pathologist at the University of Washington, Seattle, wondered whether defects in proofreading, another repair mechanism, could also faster tumors. He and his colleagues created mice with defects in one of the two DNA polymerases critical for replay. He compared those animals with another strain of mice with defects in mismatch repair. All three died of cancer, but not the same: A defective-replay strain succumbed to skin cancer, while other gastrointestinal tumors developed, such as mismatch-faulty strain
Next the Preston group mated mice. generate animals with defects in both repair mechanisms. The mice that were homozygous - in other words, animals that had inherited the defective gene from both parents - for both defective mismatch repair defective and were not born at all. Most striking were homozygous animals for mismatch repair and heterozygous for proofreading; all died of cancer, most lymphomas, 3 months of age. DNA in their cells mutated 0 times more often than normal, Preston reported here since February 13 at the annual meeting of the AAAS. "It is the highest mutation rate we've ever seen," he said.
"It is the first real evidence" that the DNA polymerases disruption can cause cancer, said Lawrence Loeb, biochemist at the University of Washington. the backup job the idea that the difficulty in repairing defects in DNA replication can cause cancer in mice, said Preston, and he and others are on the lookout for human cancers that follow this model.
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