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Originally published In Press as doi:10.1074/jbc.M109761200 on February 6, 2002

J. Biol. Chem., Vol. 277, Issue 16, 13926-13934, April 19, 2002
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In Vitro (CTG)·(CAG) Expansions and Deletions by Human Cell Extracts*

Gagan B. PanigrahiDagger , John D. ClearyDagger §, and Christopher E. PearsonDagger §||

From the Dagger  Program of Genetics and Genomic Biology, The Hospital for Sick Children, and § Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5A 1X8, Canada

The mechanism of disease-associated (CTG)·(CAG) expansion may involve DNA replication slippage, replication direction, Okazaki fragment processing, recombination, or repair. A length-dependent bias for expansions is observed in humans affected by a trinucleotide repeat-associated disease. We developed an assay to test the effect of replication direction on (CTG)·(CAG) instabilities incurred during in vitro (SV40) DNA replication mediated by human cell extracts. This system recapitulates the bias for expansions observed in humans. Replication by HeLa cell extracts generated expansions and deletions that depended upon repeat tract length and the direction of replication. Templates with 79 repeats yielded predominantly expansions (CAG as lagging strand template) or predominantly deletions (CTG as lagging strand template). Templates containing 17 repeats were stable. Thus, replication direction determined the type of mutation. These results provide new insights into the orientation of replication effect upon repeat stability. This system will be useful in determining the contribution of specific human proteins to (CTG)·(CAG) expansions.

* This work was supported in part by grants from the Muscular Dystrophy Association (United States) and the Canadian Institutes of Health Research (to C. E. P.).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.

Supported by Natural Sciences and Engineering Research Council of Canada.

|| Canadian Institutes of Health Research Scholar, a Canadian Genetic Disease Network Scholar, and a Premier's Research Excellence Award Scholar. To whom correspondence should be addressed: Genetics and Genomic Biology, The Hospital for Sick Children, 555 University Ave., Elm Wing, 11-135, Toronto, Ontario M5G 1X8, Canada. Tel.: 416-813-8256; Fax: 416-813-4931; E-mail: cepearson@genet.sickkids.on.ca.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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