Recognition and repair of compound DNA lesions (base damage and mismatch) by human mismatch repair and excision repair systems.
Nucleotide excision repair and the long-patch mismatch repair systems correct abnormal DNA structures arising from DNA damage and replication errors, respectively. DNA synthesis past a damaged base (translesion replication) often causes misincorporation at the lesion site. In addition, mismatches are hot spots for DNA damage because of increased susceptibility of unpaired bases to chemical modification. We call such a DNA lesion, that is, a base damage superimposed on a mismatch, a compound lesion. To learn about the processing of compound lesions by human cells, synthetic compound lesions containing UV photoproducts or cisplatin 1,2-d(GpG) intrastrand cross-link and mismatch were tested for binding to the human mismatch recognition complex hMutS alpha and for excision by the human excision nuclease. No functional overlap between excision repair and mismatch repair was observed. The presence of a thymine dimer or a cisplatin diadduct in the context of a G-T mismatch reduced the affinity of hMutS alpha for the mismatch. In contrast, the damaged bases in these compound lesions were excised three- to fourfold faster than simple lesions by the human excision nuclease, regardless of the presence of hMutS alpha in the reaction. These results provide a new perspective on how excision repair, a cellular defense system for maintaining genomic integrity, can fix mutations under certain circumstances.
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- Saccharomyces cerevisiae Proteins
- Pyrimidine Dimers
- Proto-Oncogene Proteins
- Proteins
- Nucleic Acid Heteroduplexes
- MutS Homolog 2 Protein
- MutL Protein Homolog 1
- Mismatch Repair Endonuclease PMS2
- Humans
- Hela Cells
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Saccharomyces cerevisiae Proteins
- Pyrimidine Dimers
- Proto-Oncogene Proteins
- Proteins
- Nucleic Acid Heteroduplexes
- MutS Homolog 2 Protein
- MutL Protein Homolog 1
- Mismatch Repair Endonuclease PMS2
- Humans
- Hela Cells