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Tuesday, 31 January 2012

Metabolic errors...DNA damage....could lead to Cancer

Metabolic errors...DNA damage....could lead to Cancer

Cells keep tight control over their purine supply, and any disruption of that pool can have serious consequences. In a new study, Massachusetts Institute of Technology (MIT) biological engineers have precisely measured the effects of errors in systems for purine production and breakdown.

DNA usually consists of a sequence of four building blocks, or nucleotides: Adenine, guanine, cytosine, and thymine (the A, G, C, and T letters that make up the genetic code). Guanine and adenine are purines, and each has a close structural relative that can take its place in DNA or RNA. When these nucleotides, known as xanthine and hypoxanthine, are mistakenly inserted into DNA, they cause mutations. They can also interfere with the function of messenger RNA (mRNA), which carries DNA’s instructions to the rest of the cell, and the RNA molecules that translate mRNA into proteins.

"A cell needs to control the concentrations very carefully so that it has just the right amount of building blocks when it’s synthesizing DNA. If the cell has an imbalance in the concentrations of those nucleotides, it’s going to make a mistake," says Peter Dedon, a professor of biological engineering at MIT and senior author of the study, which will appear in the Proceedings of the National Academy of Sciences.

They found that defects in enzymes that control these processes can severely alter a cell's DNA sequences, which may explain why people who carry certain genetic variants of purine metabolic enzymes have a higher risk for some types of cancer. Dozens of enzymes are involved in purine metabolism, and it has long been known that malfunction of those enzymes can have adverse effects. For example, losing a purine salvage enzyme, which recovers purine nucleotides from degraded DNA and RNA, leads to high blood levels of uric acid, causing gout and kidney stones—and in extreme cases, a neurological disorder called Lesch-Nyhan syndrome. Losing another salvage enzyme produces a disease called severe combined immunodeficiency.

In the new study, Dedon and his colleagues disrupted about half a dozen purine metabolism enzymes in E. coli and yeast. After altering the enzymes, the researchers measured how much xanthine and hypoxanthine was integrated into the cells' DNA and RNA. They found that the malfunctioning enzymes could produce dramatic increases—up to 1,000-fold—in the amounts of hypoxanthine incorporated into DNA and RNA in place of adenine.

Scientists have found quite a bit of genetic variation in purine metabolic enzymes in humans, so the research team plans to investigate the impact of those human variants on xanthine and hypoxanthine insertion into DNA.