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J. Biol. Chem., Vol. 277, Issue 30, 27401-27411, July 26, 2002
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From the Division of Hematology/Oncology, Department of Molecular
Biology and Microbiology, Case Western Reserve University,
Cleveland, Ohio 44106
The latency-associated nuclear antigen (LANA) of
Kaposi's sarcoma-associated herpesvirus is a multifunctional
protein with important roles in both transcriptional regulation and
episomal maintenance. LANA is also a DNA-binding protein and has been
shown to specifically bind to a region within the terminal repeat.
Here, we have performed a detailed analysis of the DNA-binding activity of LANA and show that it binds two sites separated by 22 bp. We used
electrophoretic mobility shift assay to quantitatively analyze the
binding sites and determined that the Kd of the
high affinity site is 1.51 ± 0.16 nM. Examination of
the contribution of nucleotides near the ends of the site showed that
the core binding site consists of 16 bp, 13 of which are conserved
between both sites. Analysis of the affinity of each site alone and in tandem revealed that the binding to the second site is primarily due to
cooperativity with the first site. Using deletion and point mutations,
we show that both sites contribute to the ability of LANA to suppress
transcription and to facilitate DNA replication. In addition, we show
that the ability of LANA to carry out these functions is directly
proportional to its affinity for the sites in this region. The
affinities, spacing, and cooperative binding between the two sites is
similar to that of the Epstein-Barr virus dyad symmetry element
oriP, suggesting a requirement for such an element in
latent replication of these related DNA tumor viruses.
Latency-associated Nuclear Antigen (LANA) Cooperatively Binds to
Two Sites within the Terminal Repeat, and Both Sites Contribute
to the Ability of LANA to Suppress Transcription and to Facilitate DNA
Replication*
,
*
This work was supported in part by Grant CA 88763-2 from the
National Institutes of Health (to R. R.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of Research Oncology Training Grant T32 HL 07147 from
the National Institutes of Health.
§
Mount Sinai Healthcare Foundation Scholar. To whom correspondence
should be addressed: Div. of Hematology/Oncology, Dept. of Molecular
Biology and Microbiology, BRB R301, 2109 Adelbert Rd., Case Western
Reserve University, Cleveland, OH 44106. Tel.: 216-368-1190; Fax:
216-368-1166; E-mail: rfr3@po.cwru.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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