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Team Unravels DNA Repair Protein Structure

By Anna Maria Gillis

Researchers from the National Institute of Diabetes and Digestive and Kidney Diseases have determined the structure of a bacterial protein vital to repairing DNA. The findings, which appeared in the Oct. 12 issue of Nature, could help scientists studying a comparable, but faulty, human protein associated with a hereditary colorectal cancer.

In their paper, Wei Yang and Changill Ban of the Laboratory of Molecular Biology and Peggy Hsieh and Galina Obmolova of the Genetics and Biochemistry Branch describe the structures of the protein MutS and MutS combined with DNA that were isolated from the eubacterium Thermus aquaticus. MutS is one of several proteins that work together to correct mistakes that arise when the microbe's DNA is copied. Such repair proteins, with different names, exist in all living things.

Four bases make up DNA; when DNA replicates, mismatches sometimes occur. Normally, guanine (G) pairs with cytosine (C) and adenine (A) matches with thymine (T) along the helix. At the beginning of replication, the two DNA template strands separate and daughter strands are made to complement each template strand. For instance, if a string of bases on the parent strand reads GGATTC, the corresponding stretch on the daughter strand should read CCTAAG. If the wrong nucleotide slips in on the daughter strand, mismatch repair begins.

Scientists had long known that MutS's function in bacteria was to recognize mismatches and unpaired bases between the template and daughter strand. They found that MutS worked with another protein, MutL, to activate MutH, which then snips the daughter strand up to a thousand base pairs away from the error. MutH's cut allows a fourth protein called exonuclease to come in to take out bases, including the errors, much like a computer's backspace key. But until recently, scientists couldn't demonstrate how exactly the repair proteins worked at the molecular level because they had no crystal structures of them. With a crystallized molecule, scientists get a three-dimensional view of the curves, twists and indentations on a protein that indicates how and where it binds to another protein or DNA.

Yang and her colleagues plan to use what they've learned from microbial repair proteins to create models of human proteins and solve their structures.


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