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Molecular and Cellular Biology, March 1999, p. 2206-2211, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Impaired Translesion Synthesis in Xeroderma Pigmentosum Variant Extracts

Agnes M. Cordonnier,1 Alan R. Lehmann,2 and Robert P. P. Fuchs1,*

UPR9003 du CNRS, Cancérogenèse et Mutagenèse Moléculaire et Structurale, ESBS, 67400 Strasbourg, France,1 and Medical Research Council Cell Mutation Unit, University of Sussex, Falmer, Brighton BN1 9RR, England2

Received 20 July 1998/Returned for modification 11 September 1998/Accepted 6 November 1998

Xeroderma pigmentosum variant (XPV) cells are characterized by a cellular defect in the ability to synthesize intact daughter DNA strands on damaged templates. Molecular mechanisms that facilitate replication fork progression on damaged DNA in normal cells are not well defined. In this study, we used single-stranded plasmid molecules containing a single N-2-acetylaminofluorene (AAF) adduct to analyze translesion synthesis (TLS) catalyzed by extracts of either normal or XPV primary skin fibroblasts. In one of the substrates, the single AAF adduct was located at the 3' end of a run of three guanines that was previously shown to induce deletion of one G by a slippage mechanism. Primer extension reactions performed by normal cellular extracts from four different individuals produced the same distinct pattern of TLS, with over 80% of the products resulting from the elongation of a slipped intermediate and the remaining 20% resulting from a nonslipped intermediate. In contrast, with cellular extracts from five different XPV patients, the TLS reaction was strongly reduced, yielding only low amounts of TLS via the nonslipped intermediate. With our second substrate, in which the AAF adduct was located at the first G in the run, thus preventing slippage from occurring, we confirmed that normal extracts were able to perform TLS 10-fold more efficiently than XPV extracts. These data demonstrate unequivocally that the defect in XPV cells resides in translesion synthesis independently of the slippage process.

* Corresponding author. Mailing address: UPR9003 du CNRS, Cancérogenèse et Mutagenèse Moléculaire et Structurale, ESBS, Blvd S. Brant, 67400 Strasbourg, France. Phone and Fax: 33 388 65 53 4. E-mail: fuchs{at}esbs.u-strasbourg.fr.

Molecular and Cellular Biology, March 1999, p. 2206-2211, Vol. 19, No. 3
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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