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DNA Repair (Amst). 2003 Nov 21;2(11):1199-210.

Strand-specific processing of 8-oxoguanine by the human mismatch repair pathway: inefficient removal of 8-oxoguanine paired with adenine or cytosine.

Author information

1
Department of Biology, Indiana University, Bloomington, IN 47405, USA.

Abstract

Genomic DNA and its precursors are susceptible to oxidation during aerobic cellular metabolism, and at least five distinct repair activities target a single common lesion, 7,8-dihydro-8-oxoguanine (8-oxoG). The human mismatch repair (MMR) pathway, which has been implicated in an apoptotic response to covalent DNA damage, is likely to encounter 8-oxoG in both the parental and daughter strand during replication. Here, we show that lesions containing 8-oxoG paired with adenine or cytosine, which are most likely to arise during replication, are not efficiently processed by the mismatch repair system. Lesions containing 8-oxoG paired with thymine or guanine, which are unlikely to arise, are excised in an MSH2/MSH6-dependent manner as effectively as the corresponding mismatches when placed in a context that reflects the daughter strand during replication. Using a newly developed assay based on methylation sensitivity, we characterized strand-excision events opposite 8-oxoG situated to reflect placement in the parental strand. Lesions that efficiently trigger strand excision and resynthesis (8-oxoG paired with thymine or guanine) result in adenine or cytosine insertion opposite 8-oxoG. These latter pairings are poor substrates for further action by mismatch repair, but precursors for alternative pathways with non-mutagenic outcomes. We suggest that the lesions most likely to be encountered by the human mismatch repair pathway during replication, 8-oxoG.A or 8-oxoG.C, are likely to escape processing in either strand by this system. Taken together, these data suggest that the human mismatch repair pathway is not a major contributor to removal of misincorporated 8-oxoG, nor is it likely to trigger repeated attempts at lesion processing.

PMID:
14599742
[Indexed for MEDLINE]

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