Structure and mechanism of human DNA polymerase η

Biertümpfel, Christian, Zhao, Ye, Kondo, Yuji, Ramón-Maiques, Santiago, Gregory, Mark, Lee, Jae Young, Masutani, Chikahide, Lehmann, Alan R, Hanaoka, Fumio and Yang, Wei (2010) Structure and mechanism of human DNA polymerase η. Nature, 465 (7301). pp. 1044-1048. ISSN 0028-0836

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

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: EPrints Services
Date Deposited: 06 Feb 2012 19:59
Last Modified: 03 Jul 2019 00:50

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