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Molecular and Cellular Biology, January 1999, p. 46-56, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Evidence that Protein Binding Specifies Sites of DNA Demethylation

Chih-Lin Hsieh*

Department of Urology and Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, California 90033

Received 9 June 1998/Returned for modification 11 August 1998/Accepted 17 September 1998

It has been hypothesized that protein factors may protect CpG islands from methyltransferase during development and that demethylation may involve protein-DNA interactions at demethylated sites. However, direct evidence has been lacking. In this study, demethylation at the EBNA-1 binding sites of the Epstein-Barr virus latent replication origin, oriP, was investigated by using human cells. Several novel findings are discussed. First, there are specific preferential demethylation sites within the oriP region. Second, the DNA sequence of oriP alone is not the target of an active demethylation process. Third, EBNA-1 binding is required for the site-specific demethylation in oriP. Interestingly, CpG sites adjacent to and between the EBNA-1 sites do not become demethylated. Fourth, demethylation of the first DNA strand in oriP at the EBNA-1 binding sites involves a passive (replication-dependent) mechanism. The second-strand demethylation appears to occur through an active mechanism. That is, EBNA-1 protein binding prevents the EBNA-1 binding sites from being remethylated after one round of DNA replication, and it appears that an active demethylase then demethylates these hemimethylated sites. This study provides clear evidence that protein binding specifies sites of DNA demethylation and provides insights into the sequence of steps and the mechanism of demethylation.

* Mailing address: Department of Urology and Department of Biochemistry and Molecular Biology, University of Southern California, 1441 Eastlake Ave., Room 5420, Norris Cancer Center, Mail Stop #73, Los Angeles, CA 90033. Phone: (323) 865-0567. Fax: (323) 865-3019. E-mail: hsieh_c{at}froggy.hsc.usc.edu.

Molecular and Cellular Biology, January 1999, p. 46-56, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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