NEWS OF THljfflEEEffi BIOCHEMISTRY
REPAIR ENZYME FLIPS AND SNIPS Structure fills out picture of how cells carry out error-free repair of DNA
T
HE PROCESS BY W H I C H
cells correct the damage done to DNA by reactive oxygen species just got a little clearer, thanks to a new structure of the repair enzyme MutY bound to its damaged substrate. Produced by everything from smoking to normal metabolic activity, reactive oxygen species are constantly damaging the nucleotide bases that make up genomic DNA. One of the most common types of damage is the conversion of guanine to 8-oxoguanine (8-oxoG). If allowed to persist, 8-oxoG lesions will pair with adenine—not cytosine, guanine's normal partner—during DNA replication. 8-OxoGAmispairs eventually giveriseto dangerous genetic mutations, so cells have devised away to repair both bases to restore the originalDNAsequence. MutYcarries out thefirststep ofthis process: finding 8-oxoG :Amispairs and removing the adenine. "How MutY distinguishes A residues paired abnormally with 8-oxoG amidst the vast excess of Aresidues paired normally withT {thymine} has been a long-standing question in the field," notes Harvard University chemistryprofessor Gregory L. Verdine. Verdine, graduate student J. Christopher Fromme, and their coworkers have now neatly answered this question by solving a 2.2-Â X-ray structure of MutY bound to DNA containing an 8oxoG:Aimspm[Nature, 427,652 (2004)}. None of the half dozen hydrogen bonds that the enzyme makes to the 8-oxoG in this structure would be possible with a thymine, Verdine points out. HTTP://WWW.CEN-ONLINE.ORG
The structure also reveals how MutYremoves the unwanted adenine. MutYcreates a sharp bend in the DNA at the site of the 8-oxoGA mispair. It then extrudes the adenine into its active site and clips the base from the DNAbackbone. Calling the research a "tour de force," chemistry professor Sheila S. David of the University ofUtah notes that Verdine's team used a number of clever tricks to stabilize the normally fragile complex, including using a hardy version of MutY from a thermophilic bacterium and crosslinking the enzyme to the DNA substrate via a disulfide bond. A team led by David previously showed that two different inherited mutations in Myh—the human version of MutY—pre-
CUT IT OUT The repair enzyme MutY (gray) bends the DNA helix (gold) while searching for adenine residues that are mispaired with the damaged base 8-oxoguanine (yellow). To fix such mismatches, MutY extrudes the adenine (red) into its active site and clips the base from the DNA backbone. Other enzymes then pitch in to restore the original DNA sequence.
dispose patients to colon cancer. She points out that the new structure explains why these mutations impair Myh's activity, allowing cancer-causing 8-oxoG:A mispairs to persist. In both cases, the amino acid that's mutated normally plays an important role in recognizing 8-oxoG, Verdine's team reports.-AMANDA YARN ELL
NATIONAL SCIENCE
FOUNDATION
Colwell Retires As Director Of Science Agency
R
ita R. Colwell has announced that she will retire as director of NSF, effective Feb. 21. She will leave six months before the end of her six-year term at NSF to become chairman of Washington, D.C.-based Canon U.S. Life Sciences, a newly created subsidiary of Canon U.S.A. Colwell, 69, a microbiologist and expert on cholera and other infectious diseases, will also hold faculty positions at the University of Maryland and Johns Hopkins Bloomberg School of Public Health. "I am extremely grateful to have had the opportunity to lead NSF through two Administrations and major transformational change," Colwell said in a statement. During her tenure, she has helped raise the aver-
age grant size from $90,000 to $142,000. She has also supported interdisciplinary collaborations, increases in graduate student stipends, and more opportunities for women and minorities in science and engineering. "Starting with a budget of about $3.4 billion, she is now arguing before Congress for an NSF budget of more than $5.7 billion," says Richard N. Zare, chemistry professor at Stanford University and chairman of the National Science Board from 1996 to 1998. "In addition, she should be given credit for making a number of key appointments." National Institute of Standards & Technology Director Arden L Bernent Jr. is expected to be named acting director for the remainder of Colwell's term.-SUSAN MORRISSEY
C&EN
/ FEBRUARY
16, 2004
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