Structure and mechanism of human DNA polymerase

Christian Biertümpfel, Ye Zhao, Yuji Kondo, Santiago Ramón-Maiques, Mark Gregory, Jae Young Lee, Chikahide Masutani, Alan R. Lehmann, Fumio Hanaoka, Wei Yang

Research output: Contribution to journalArticlepeer-review

285 Scopus citations

Abstract

The variant form of the human syndrome xeroderma pigmentosum (XPV) is caused by a deficiency in DNA polymerase (Pol), a DNA polymerase that enables replication through ultraviolet-induced pyrimidine dimers. Here we report high-resolution crystal structures of human Pol at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Pol acts like a gη molecular splintgη 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 Pol orthologues form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. On the basis of the structures, eight Pol 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 Pol in replicating through D loop and DNA fragile sites.

Original languageEnglish
Pages (from-to)1044-1048
Number of pages5
JournalNature
Volume465
Issue number7301
DOIs
StatePublished - 24 Jun 2010

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