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Structural basis for the suppression of skin cancers by DNA polymerase η


DNA polymerase η (Polη) is unique among eukaryotic polymerases in its proficient ability for error-free replication through ultraviolet-induced cyclobutane pyrimidine dimers, and inactivation of Polη (also known as POLH) in humans causes the variant form of xeroderma pigmentosum (XPV). We present the crystal structures of Saccharomyces cerevisiae Polη (also known as RAD30) in ternary complex with a cis-syn thymine-thymine (T-T) dimer and with undamaged DNA. The structures reveal that the ability of Polη to replicate efficiently through the ultraviolet-induced lesion derives from a simple and yet elegant mechanism, wherein the two Ts of the T-T dimer are accommodated in an active site cleft that is much more open than in other polymerases. We also show by structural, biochemical and genetic analysis that the two Ts are maintained in a stable configuration in the active site via interactions with Gln 55, Arg 73 and Met 74. Together, these features define the basis for Polη’s action on ultraviolet-damaged DNA that is crucial in suppressing the mutagenic and carcinogenic consequences of sun exposure, thereby reducing the incidence of skin cancers in humans.

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Figure 1: Polη–DNA–dATP ternary complexes.
Figure 2: Close-up views of the active site regions.
Figure 3: Conformational changes in Polη ternary complex.
Figure 4: Comparison between Polη and Polκ.

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Protein Data Bank

Data deposits

Atomic coordinates and structure factors files have been deposited in the Protein Data Bank under accession codes 3MFH and 3MFI.


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We thank the staff at Brookhaven National Laboratory (beamlines X6A and X29) and the Advanced Photon Source (24ID) for facilitating X-ray data collection. We thank D. T. Nair, S. Lone, R. Vasquez-Del Carpio and M. Swan for discussions. This work was supported by NIH grants to A.K.A., S.P. and L.P.

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Authors and Affiliations



A.K.A. and T.D.S. designed the crystallographic studies; S.P., L.P. and R.E.J. designed the biochemical and genetic studies; T.D.S., R.E.J., R.J. and L.P. performed the experiments; all of the authors contributed to the writing of the paper.

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Correspondence to Satya Prakash or Aneel K. Aggarwal.

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The authors declare no competing financial interests.

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Silverstein, T., Johnson, R., Jain, R. et al. Structural basis for the suppression of skin cancers by DNA polymerase η. Nature 465, 1039–1043 (2010).

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