Martin MarinusDepartment of Pharmacology and Molecular Toxicology, University of Massachusetts Medical School, Worcester, Massachusetts, USA F1000 Faculty Member (since 04 July 2001)
DNA Repair and Recombination
Recombinational Repair of Drug-Induced Damage. Cells have repair mechanisms that protect their DNA from the action of various cytotoxic agents. The agents we have studied are cisplatin, methylating agents and bleomycin, which are antitumor agents, and nitric oxide, which is thought to produce free radical damage to DNA. Although these compounds produce different types of DNA damage, we have found that homologous recombination is required to efficiently repair damage caused by these agents.
DNA Methylation. Dam methyltransferase forms N6-methyladenine in GATC sequences in Escherichia coli. Such methylation is important for regulation of gene expression, initiation of chromosome replication and directionality of mismatch repair.
In enterohemorrhagic E. coli, dam mutants show dramatic increases in adherence and and actin pedestal formation to cultured human cells compared to wildtype. This increase is accompanied by enhanced levels of certain virulence factors although the mRNA transcript levels of these factors are the same as wildtype. We are currently exploring the mechanism of this post-transcriptional effect.
We have used oligonucleotide microarrays to determine global transcription patterns in cells with varying levels of Dam and SeqA proteins. The SeqA protein binds to a subset of dam sites. The results indicate that DNA methylation status of the cell is an important factor in forming and/or maintaining chromosome structure.
DNA Mismatch Repair and Antirecombination. Cells use mismatch repair to correct replication errors and a subset of mismatch repair proteins for antirecombination which prevents recombination between closely related DNA sequences. MutS protein, which is a multimer, binds to DNA mismatches to initiate either mismatch repair or antirecombination. To determine if specific MutS multimeric forms are important for function, we are characterizing mutant derivatives of MutS that have monomeric or different multimeric forms for their ability to perform mismatch repair or antirecombination.
Mismatch Repair-Induced Cell Death. Dam mutant cells are more sensitive to cisplatin and methylating agents than wildtype cells. If mismatch repair capacity is inactivated, however, the cells become resistant to these drugs. We are investigating the mechanism by which mismatch repair sensitizes cells to the action of these drugs.
B.Sc.(Hons.), 1965, PhD, Otago, New Zealand, 1968
American Cancer Society Faculty Research Award, 1976-1981
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F1000 Biology Reports 2010 2:(56) (22 Jul 2010)
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