Structure and mechanism of human DNA polymerase η

Christian Biertümpfel, Ye Zhao, Yuji Kondo, Santiago Ramón-Maiques, Mark Gregory, Jae Young Lee, Chikahide Masutani, Alan R. Lehmann, Fumio Hanaoka () and Wei Yang ()
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Christian Biertümpfel: Laboratory of Molecular Biology, NIDDK, NIH, 9000 Rockville Pike, Building 5, Room B103, Bethesda, Maryland 20892, USA
Ye Zhao: Laboratory of Molecular Biology, NIDDK, NIH, 9000 Rockville Pike, Building 5, Room B103, Bethesda, Maryland 20892, USA
Yuji Kondo: Graduate School of Frontier Biosciences, Osaka University
Santiago Ramón-Maiques: Laboratory of Molecular Biology, NIDDK, NIH, 9000 Rockville Pike, Building 5, Room B103, Bethesda, Maryland 20892, USA
Mark Gregory: Laboratory of Molecular Biology, NIDDK, NIH, 9000 Rockville Pike, Building 5, Room B103, Bethesda, Maryland 20892, USA
Jae Young Lee: Laboratory of Molecular Biology, NIDDK, NIH, 9000 Rockville Pike, Building 5, Room B103, Bethesda, Maryland 20892, USA
Chikahide Masutani: Graduate School of Frontier Biosciences, Osaka University
Alan R. Lehmann: Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK
Fumio Hanaoka: Graduate School of Frontier Biosciences, Osaka University
Wei Yang: Laboratory of Molecular Biology, NIDDK, NIH, 9000 Rockville Pike, Building 5, Room B103, Bethesda, Maryland 20892, USA

Nature, 2010, vol. 465, issue 7301, 1044-1048

Abstract: Abstract The variant form of the human syndrome xeroderma pigmentosum (XPV) is caused by a deficiency in DNA polymerase η (Polη), a DNA polymerase that enables replication through ultraviolet-induced pyrimidine dimers. Here we report high-resolution crystal structures of human Polη at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Polη acts like a ‘molecular splint’ to stabilize damaged DNA in a normal B-form conformation. An enlarged active site accommodates the thymine dimer with excellent stereochemistry for two-metal ion catalysis. Two residues conserved among Polη orthologues form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. On the basis of the structures, eight Polη missense mutations causing XPV can be rationalized as undermining the molecular splint or perturbing the active-site alignment. The structures also provide an insight into the role of Polη in replicating through D loop and DNA fragile sites.

Date: 2010
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DOI: 10.1038/nature09196

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