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Molecular and Cellular Biology, June 2002, p. 4390-4401, Vol. 22, No. 12
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.12.4390-4401.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The DNA Architectural Protein HMGB1 Displays Two Distinct Modes of Action That Promote Enhanceosome Assembly

Katherine Mitsouras, Ben Wong, Charina Arayata, Reid C. Johnson, and Michael Carey*

Department of Biological Chemistry, UCLA School of Medicine, Los Angeles, California 90095-1737

Received 24 October 2001/ Returned for modification 9 January 2002/ Accepted 18 March 2002

HMGB1 (also called HMG-1) is a DNA-bending protein that augments the affinity of diverse regulatory proteins for their DNA sites. Previous studies have argued for a specific interaction between HMGB1 and target proteins, which leads to cooperative binding of the complex to DNA. Here we propose a different model that emerged from studying how HMGB1 stimulates enhanceosome formation by the Epstein-Barr viral activator Rta on a target gene, BHLF-1. HMGB1 stimulates binding of individual Rta dimers to multiple sites in the enhancer. DNase I and hydroxyl radical footprinting, electrophoretic mobility shift assays, and immobilized template assays failed to reveal stable binding of HMGB1 within the complex. Furthermore, mutational analysis failed to identify a specific HMGB1 target sequence. The effect of HMGB1 on Rta could be reproduced by individual HMG domains, yeast HMO1, or bacterial HU. These results, combined with the effects of single-amino-acid substitutions within the DNA-binding surface of HMGB1 domain A, argue for a mechanism whereby DNA-binding and bending by HMGB1 stimulate Rta-DNA complex formation in the absence of direct interaction with Rta or a specific HMGB1 target sequence. The data contrast with our analysis of HMGB1 action on another BHLF-1 regulatory protein called ZEBRA. We discuss the two distinct modes of HMGB1 action on a single regulatory region and propose how HMGB1 can function in diverse contexts.

* Corresponding author. Mailing address: Department of Biological Chemistry, UCLA School of Medicine, Box 1737, Los Angeles CA, 90095-1737. Phone: (310) 206-7859. Fax: (310) 206-9598. E-mail: mcarey{at}mednet.ucla.edu.

Molecular and Cellular Biology, June 2002, p. 4390-4401, Vol. 22, No. 12
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.12.4390-4401.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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