Published online 21 December 2004
Nucleic Acids Research, Vol. 32 No. 22 © Oxford University Press 2004; all rights reserved
Short-patch correction of C/C mismatches in human cells
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, 8057 Zürich, Switzerland and 1 Institute of Molecular Cancer Research, University of Zürich, 8008 Zürich, Switzerland
* To whom correspondence should be addressed. Tel: +41 1 635 8763; Fax: +41 1 635 8910; Email: naegelih{at}vetpharm.unizh.ch
Received September 3, 2004; Revised and Accepted November 22, 2004
We examined whether the human nucleotide excision repair complex, which is specialized on the removal of bulky DNA adducts, also displays a correcting activity on base mismatches. The cytosine/cytosine (C/C) lesion was used as a model substrate to monitor the correction of base mismatches in human cells. Fibroblasts with different repair capabilities were transfected with shuttle vectors that contain a site-directed C/C mismatch in the replication origin, accompanied by an additional C/C mismatch in one of the flanking sequences that are not essential for replication. Analysis of the vector progeny obtained from these doubly modified substrates revealed that C/C mismatches were eliminated before DNA synthesis not only in the repair-proficient background, but also when the target cells carried a genetic defect in long-patch mismatch repair, in nucleotide excision repair, or when both pathways were deleted. Furthermore, cells deficient for long-patch mismatch repair as well as a cell line that combines mismatch and nucleotide excision repair defects were able to correct multiple C/C mispairs, placed at distances of 21–44 nt, in an independent manner, such that the removal of each lesion led to individual repair patches. These results support the existence of a concurrent short-patch mechanism that rectifies C/C mismatches.
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