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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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