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Molecular and Cellular Biology, April 2000, p. 2446-2454, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

DNA Interstrand Cross-Links Induce Futile Repair Synthesis in Mammalian Cell Extracts

David Mu,1 Tadayoshi Bessho,1 Lubomir V. Nechev,2 David J. Chen,3 Thomas M. Harris,2 John E. Hearst,4 and Aziz Sancar1,*

Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-72601; Life Sciences Division2 and Department of Chemistry,4 Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720; and Department of Chemistry, Vanderbilt University, Nashville, Tennessee 372323

Received 1 December 1999/Returned for modification 4 January 2000/Accepted 6 January 2000

DNA interstrand cross-links are induced by many carcinogens and anticancer drugs. It was previously shown that mammalian DNA excision repair nuclease makes dual incisions 5' to the cross-linked base of a psoralen cross-link, generating a gap of 22 to 28 nucleotides adjacent to the cross-link. We wished to find the fates of the gap and the cross-link in this complex structure under conditions conducive to repair synthesis, using cell extracts from wild-type and cross-linker-sensitive mutant cell lines. We found that the extracts from both types of strains filled in the gap but were severely defective in ligating the resulting nick and incapable of removing the cross-link. The net result was a futile damage-induced DNA synthesis which converted a gap into a nick without removing the damage. In addition, in this study, we showed that the structure-specific endonuclease, the XPF-ERCC1 heterodimer, acted as a 3'-to-5' exonuclease on cross-linked DNA in the presence of RPA. Collectively, these observations shed some light on the cellular processing of DNA cross-links and reveal that cross-links induce a futile DNA synthesis cycle that may constitute a signal for specific cellular responses to cross-linked DNA.

* Corresponding author. Mailing address: Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7260. Phone: (919) 962-0115. Fax: (919) 843-8627.

Molecular and Cellular Biology, April 2000, p. 2446-2454, Vol. 20, No. 7
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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