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Nucleic Acids Research Advance Access published online on May 3, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm166
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© 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.

Structural Biology

Transcription activator structure reveals redox control of a replication initiation reaction{dagger}

Cyril M. Sanders1,*, Dmytro Sizov2, Philippa R. Seavers2, Miguel Ortiz-Lombardía2 and Alfred A. Antson2

1Institute for Cancer Studies, University of Sheffield, Beech Hill Rd, Sheffield, S10 2RX, UK and 2York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York, YO10 5YW, UK

*To whom correspondence should be addressed. Tel: +44-114-271-2482; Fax: +44-114-271-3892; Email: c.m.sanders{at}sheffield.ac.uk

Received November 10, 2006. Revised January 26, 2007. Accepted March 5, 2007.

Redox changes are one of the factors that influence cell-cycle progression and that control the processes of cellular proliferation, differentiation, senescence and apoptosis. Proteins regulated through redox-sensitive cysteines have been characterized but specific ‘sulphydryl switches’ in replication proteins remain to be identified. In bovine papillomavirus type-1, DNA replication begins when the viral transcription factor E2 recruits the viral initiator protein E1 to the origin of DNA replication (ori). Here we show that a novel dimerization interface in the E2 transcription activation domain is stabilized by a disulphide bond. Oxidative cross-linking via Cys57 sequesters the interaction surface between E1 and E2, preventing pre-initiation and replication initiation complex formation. Our data demonstrate that as well as a mechanism for regulating DNA binding, redox reactions can control replication by modulating the tertiary structure of critical protein factors using a specific redox sensor.

Present address: Dmytro Sizov, Taras Shevchenko Kiev State University, Biology Faculty, Virology Department, Glushkova Ave. 2, 03127 Kiev, Ukraine.

Present address: Miguel Oritiz-Lombardía, Centro Nacional de Investigaciones Oncológicas, Programa de Biología Estructural y Biocomputación, C. Melchor Fernández Almagro 3, Madrid 28029, Spain.

{dagger}The coordinates and structure factors of the wild-type BPV TAD and R172A mutant have been deposited with the Protein Data Bank under accession codes 2jeu and 2jex, respectively.


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