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Nucleic Acids Research Advance Access originally published online on December 15, 2007
Nucleic Acids Research 2008 36(3):756-769; doi:10.1093/nar/gkm1104
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Nucleic Acids Research, 2008, Vol. 36, No. 3 756-769
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genomics

Comprehensive comparison of the interaction of the E2 master regulator with its cognate target DNA sites in 73 human papillomavirus types by sequence statistics

Ignacio E. Sánchez1, Mariano Dellarole1, Kevin Gaston2 and Gonzalo de Prat Gay1,*

1Fundación Instituto Leloir and IIBBA-Conicet, Patricias Argentinas 435 (1405), Buenos Aires, Argentina and 2Department of Biochemistry, University of Bristol, Bristol BS8 1TD, UK

*To whom correspondence should be addressed. Tel: +54 11 5238 7500 ext. 3209; Fax: +54 11 5238 7501; Email: gpratgay{at}leloir.org.ar

Received September 11, 2007. Revised October 23, 2007. Accepted November 27, 2007.

Mucosal human papillomaviruses (HPVs) are etiological agents of oral, anal and genital cancer. Properties of high- and low-risk HPV types cannot be reduced to discrete molecular traits. The E2 protein regulates viral replication and transcription through a finely tuned interaction with four sites at the upstream regulatory region of the genome. A computational study of the E2–DNA interaction in all 73 types within the alpha papillomavirus genus, including all known mucosal types, indicates that E2 proteins have similar DNA discrimination properties. Differences in E2–DNA interaction among HPV types lie mostly in the target DNA sequence, as opposed to the amino acid sequence of the conserved DNA-binding alpha helix of E2. Sequence logos of natural and in vitro selected sites show an asymmetric pattern of conservation arising from indirect readout, and reveal evolutionary pressure for a putative methylation site. Based on DNA sequences only, we could predict differences in binding energies with a standard deviation of 0.64 kcal/mol. These energies cluster into six discrete affinity hierarchies and uncovered a fifth E2-binding site in the genome of six HPV types. Finally, certain distances between sites, affinity hierarchies and their eventual changes upon methylation, are statistically associated with high-risk types.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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