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Biological Chemistry

Enzyme Structure And Mutations Reveal Disease Roles

June 9, 2008 | APPEARED IN VOLUME 86, ISSUE 23

The structure determination and mutational analysis of XPD helicase, a key DNA repair enzyme, have yielded molecular insights into its roles in cancer and aging. The work could lead to therapies for three inherited conditions: xeroderma pigmentosum (XP), a syndrome that boosts the risk of developing skin cancer, and the premature aging and developmental disorders Cockayne syndrome (CS) and trichothiodystrophy (TTD). XPD helicase locates DNA damage and uses energy from adenosine triphosphate (ATP) to unwind DNA for repair. John A. Tainer and coworkers at Scripps Research Institute and Lawrence Berkeley National Laboratory characterized the structure of native XPD helicase and the activities of mutant versions; James H. Naismith, Malcolm F. White, and coworkers at the University of St. Andrews, in Scotland, independently determined the enzyme structure (Cell 2008, 133, 789 and 801). The work shows that on a molecular level XP-related mutations disable DNA or ATP binding; mutants that cause both XP and CS lose activity by getting “stuck” on DNA; and TTD mutations make the enzyme more flexible, possibly preventing it from interacting with protein partners.

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