Replication of a cis–syn thymine dimer at atomic resolution

Hong Ling, François Boudsocq, Brian S. Plosky, Roger Woodgate and Wei Yang ()
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Hong Ling: National Institute of Diabetes and Digestive and Kidney Diseases
François Boudsocq: National Institute of Child Health and Human Development, National Institutes of Health
Brian S. Plosky: National Institute of Child Health and Human Development, National Institutes of Health
Roger Woodgate: National Institute of Child Health and Human Development, National Institutes of Health
Wei Yang: National Institute of Diabetes and Digestive and Kidney Diseases

Nature, 2003, vol. 424, issue 6952, 1083-1087

Abstract: Abstract Ultraviolet light damages DNA by catalysing covalent bond formation between adjacent pyrimidines, generating cis–syn cyclobutane pyrimidine dimers (CPDs) as the most common lesion1. CPDs block DNA replication by high-fidelity DNA polymerases, but they can be efficiently bypassed by the Y-family DNA polymerase pol η2,3. Mutations in POLH encoding pol η are implicated in nearly 20% of xeroderma pigmentosum, a human disease characterized by extreme sensitivity to sunlight and predisposition to skin cancer4,5,6. Here we have determined two crystal structures of Dpo4, an archaeal pol η homologue, complexed with CPD-containing DNA, where the 3′ and 5′ thymine of the CPD separately serves as a templating base. The 3′ thymine of the CPD forms a Watson–Crick base pair with the incoming dideoxyATP, but the 5′ thymine forms a Hoogsteen base pair with the dideoxyATP in syn conformation. Dpo4 retains a similar tertiary structure, but each unusual DNA structure is individually fitted into the active site for catalysis. A model of the pol η–CPD complex built from the crystal structures of Saccharomyces cerevisiae apo-pol η and the Dpo4–CPD complex suggests unique features that allow pol η to efficiently bypass CPDs.

Date: 2003
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DOI: 10.1038/nature01919

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