Metabolic errors can spell doom for DNA

Jan 31, 2012 by Anne Trafton
The molecular structure of guanine (foreground) and adenine are shown.

Many critical cell functions depend on a class of molecules called purines, which form half of the building blocks of DNA and RNA, and are a major component of the chemicals that store a cell’s energy. Cells keep tight control over their purine supply, and any disruption of that pool can have serious consequences.

In a new study, MIT biological engineers have precisely measured the effects of errors in systems for purine production and breakdown. They found that defects in enzymes that control these processes can severely alter a cell’s sequences, which may explain why people who carry certain genetic variants of purine metabolic enzymes have a higher risk for some types of cancer.

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 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 is appearing in the Proceedings of the National Academy of Sciences the week of Jan. 30.

In addition to forming the backbone of DNA and RNA, purines are also a major component of ATP, the cell’s energy currency; other that manage a cell’s energy flow; and small cofactors required for the activity of thousands of cell enzymes.

Abnormal metabolism

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.

Abnormal purine metabolism can also lead to side effects for people taking a class of drugs called thiopurines. In some people, these drugs, often used to treat leukemia, lymphoma, Crohn’s disease, rheumatoid arthritis and organ-transplant rejection, can be metabolized into toxic compounds. Genetic testing can reveal which patients should avoid thiopurine drugs.

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, using a highly sensitive mass spectrometry technique they had previously developed to study DNA and RNA damage caused by inflammation.

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. However, they saw very little change in the amount of xanthine inserted in place of guanine. 

Chris Mathews, a professor emeritus of biochemistry and biophysics at Oregon State University, says the finding could help researchers better understand how defects in purine metabolism produce disease. “This paper opens the door to numerous studies — for example, looking into the biological effects resulting from the accumulation of abnormal bases in DNA and RNA,” says Mathews, who was not involved in this study.

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. They are also interested in studying the metabolism of the other two nucleotides found in DNA, cytosine and thymine, which are pyrimidines.

Explore further: Researchers capture picture of microRNA in action

Related Stories

Biologists uncover a novel cellular proofreading mechanism

Nov 11, 2011

( -- To make proteins, cells assemble long chains of amino acids, based on genetic instructions from DNA. That construction takes place in a tiny cellular structure called a ribosome, to which amino acids are ...

Recommended for you

Researchers capture picture of microRNA in action

15 hours ago

Biologists at The Scripps Research Institute (TSRI) have described the atomic-level workings of "microRNA" molecules, which control the expression of genes in all animals and plants.

Blocking a fork in the road to DNA replication

17 hours ago

A team of Whitehead Institute scientists has discovered the surprising manner in which an enigmatic protein known as SUUR acts to control gene copy number during DNA replication. It's a finding that could shed new light on ...

Cell division, minus the cells

20 hours ago

( —The process of cell division is central to life. The last stage, when two daughter cells split from each other, has fascinated scientists since the dawn of cell biology in the Victorian era. ...

A new method simplifies the analysis of RNA structure

20 hours ago

To understand the function of an RNA molecule, similar to the better-known DNA and vital for cell metabolism, we need to know its three-dimensional structure. Unfortunately, establishing the shape of an RNA ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.