The cell cycle and DNA mismatch repair
- Department of Biochemistry and Cancer Biology, Medical University of Ohio, 3035 Arlington Ave, Toledo, OH 43614-5804 (United States)
The DNA mismatch repair (MMR) pathway contributes to the fidelity of DNA synthesis and recombination by correcting mispaired nucleotides and insertion/deletion loops (IDLs). We have investigated whether MMR protein expression, activity, and subcellular location are altered during discrete phases of the cell cycle in mammalian cells. Two distinct methods have been used to demonstrate that although physiological MMR protein expression, mismatch binding, and nick-directed MMR activity within the nucleus are at highest levels during S phase, MMR is active throughout the cell cycle. Despite equal MMR nuclear protein concentrations in S and G{sub 2} phases, mismatch binding and repair activities within G{sub 2} are significantly lower, indicating a post-translational decrease in MMR activity specific to G{sub 2}. We further demonstrate that typical co-localization of MutS{alpha} to late S phase replication foci can be disrupted by 2 {mu}M N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). This concentration of MNNG does not decrease ongoing DNA synthesis nor induce cell cycle arrest until the second cell cycle, with long-term colony survival decreased by only 24%. These results suggest that low level alkylation damage can selectively disrupt MMR proofreading activity during DNA synthesis and potentially increase mutation frequency within surviving cells.
- OSTI ID:
- 20972104
- Journal Information:
- Experimental Cell Research, Vol. 313, Issue 2; Other Information: DOI: 10.1016/j.yexcr.2006.10.018; PII: S0014-4827(06)00436-8; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
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