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Originally published In Press as doi:10.1074/jbc.M104697200 on June 18, 2001

J. Biol. Chem., Vol. 276, Issue 33, 30878-30884, August 17, 2001
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Involvement of the Nucleotide Excision Repair Protein UvrA in Instability of CAG·CTG Repeat Sequences in Escherichia coli*

Elena A. OussatchevaDagger , Vera I. HashemDagger , Yue Zou§, Richard R. SindenDagger , and Vladimir N. PotamanDagger

From the Dagger  Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030, and § Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, Texas 77555

Several human genetic diseases have been associated with the genetic instability, specifically expansion, of trinucleotide repeat sequences such as (CTG)n·(CAG)n. Molecular models of repeat instability imply replication slippage and the formation of loops and imperfect hairpins in single strands. Subsequently, these loops or hairpins may be recognized and processed by DNA repair systems. To evaluate the potential role of nucleotide excision repair in repeat instability, we measured the rates of repeat deletion in wild type and excision repair-deficient Escherichia coli strains (using a genetic assay for deletions). The rate of triplet repeat deletion decreased in an E. coli strain deficient in the damage recognition protein UvrA. Moreover, loops containing 23 CTG repeats were less efficiently excised from heteroduplex plasmids after their transformation into the uvrA- strain. As a result, an increased proportion of plasmids containing the full-length repeat were recovered after the replication of heteroduplex plasmids containing unrepaired loops. In biochemical experiments, UvrA bound to heteroduplex substrates containing repeat loops of 1, 2, or 17 CAG repeats with a Kd of about 10-20 nM, which is an affinity about 2 orders of magnitude higher than that of UvrA bound to the control substrates containing (CTG)n·(CAG)n in the linear form. These results suggest that UvrA is involved in triplet repeat instability in cells. Specifically, UvrA may bind to loops formed during replication slippage or in slipped strand DNA and initiate DNA repair events that result in repeat deletion. These results imply a more comprehensive role for UvrA, in addition to the recognition of DNA damage, in maintaining the integrity of the genome.

* This work was supported by National Institutes of Health Grant ES05508 (to R. R. S.) and a grant from the Texas A&M University System Health Science Center Council on Tobacco and Environmental Health Research (to V. N. 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.

To whom correspondence should be addressed: Institute of Biosciences and Technology, Texas A&M University System Health Science Center, 2121 W. Holcombe Blvd., Houston, TX 77030.Tel.: 713-677-7675; Fax: 713-677-7689; E-mail: vpotaman@ibt.tamu.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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