# Michael D. Topal
**Michael D. Topal's** papers in *Nature* include "Complementary base pairing and the origin of substitution mutations" (1976),[2](https://doi.org/10.1038/263285a0) work showing that the pool of DNA precursors is a significant target for chemical mutagens (1982),[3](https://doi.org/10.1038/298863a0) and "Mechanism of mutagenesis by O6-methylguanine" (1984), which proposed that the lesion mutates by pairing with thymine.[4](https://doi.org/10.1038/308201a0)
| Fact | Detail |
|---|---|
| Signature work | "Complementary base pairing and the origin of substitution mutations," *Nature*, 1976[2](https://doi.org/10.1038/263285a0) |
| Central finding | O6-methylguanine mutates by pairing with thymine during replication; the lesion is repaired by O6-methylguanine-DNA methyltransferase[4](https://doi.org/10.1038/308201a0) • [5](https://doi.org/10.1093/carcin/5.12.1733) |
## Education and career
Topal earned a bachelor's degree at [Adelphi University](https://www.edgepedia.org/adelphi-university) in 1967 and a doctorate at New York University in 1972.[1](https://prabook.com/web/michael_david.topal/71310) He then spent five years as a postdoctoral fellow at Princeton University, from 1972 to 1977, holding a [National Cancer Institute](https://www.edgepedia.org/national-cancer-institute) fellowship there from 1974 to 1977.[1](https://prabook.com/web/michael_david.topal/71310)
In 1977 he moved to the [University of North Carolina at Chapel Hill](https://www.edgepedia.org/university-of-north-carolina-at-chapel-hill) as an assistant professor. He was promoted to associate professor in 1984 and to professor in 1990.[1](https://prabook.com/web/michael_david.topal/71310) His laboratory of the early 1980s was based in the Department of Pathology and the Cancer Research Center of the UNC Medical School,[6](https://www.pnas.org/doi/abs/10.1073/pnas.79.7.2211) and a Leukemia Society of America Scholar award supported his laboratory from 1984 to 1989.[1](https://prabook.com/web/michael_david.topal/71310)
## Representative work
The 1976 *Nature* paper ["Complementary base pairing and the origin of substitution mutations"](https://doi.org/10.1038/263285a0) appeared together with its companion paper on base pairing and fidelity in codon–anticodon interaction in the same 1976 volume of *Nature*.[7](https://doi.org/10.1093/carcin/9.5.691)
## The DNA precursor pool and O6-methylguanine
**The precursor pool as a mutagen target.** In 1982 his laboratory reported in *PNAS* that purine nucleotide residues in the DNA precursor pool of C3H/10T1/2 clone 8 cells are 190 to 13,000 times more susceptible to methylation by N-methyl-N-nitrosourea than the same residues in the [DNA helix](https://www.edgepedia.org/nucleic-acid-double-helix), depending on the site modified; the N-1 position of adenine in dATP was methylated 6.3 times more than the same position in DNA even though the pool's adenine content is only 0.0005 of that of the helix.[6](https://www.pnas.org/doi/abs/10.1073/pnas.79.7.2211) Methylated nucleotide products were incorporated into DNA during replication by bacteriophage T4 DNA polymerase in vitro, supporting the proposal that the precursor pool is a significant in vivo target for chemical mutagens.[6](https://www.pnas.org/doi/abs/10.1073/pnas.79.7.2211) An August 1982 *Nature* paper turned this question into a sequencing method, applying [DNA sequencing](https://www.edgepedia.org/dna-sequencing) to identify DNA precursors in chemical mutagenesis.[3](https://doi.org/10.1038/298863a0)
**How O6-methylguanine mutates.** A 1983 *Carcinogenesis* study showed that O6-methyl-dGTP incorporates opposite T and C template residues with a greater than 20-fold preference for T, and arrests DNA synthesis when incorporated in place of dATP at all but pyrimidine-rich growing-strand sequences.[8](https://doi.org/10.1093/carcin/4.12.1591) The March 1984 *Nature* paper ["Mechanism of mutagenesis by O6-methylguanine"](https://doi.org/10.1038/308201a0) set out the mechanism this implies: the lesion mispairs with thymine. Later work in his laboratory showed that the repair protein O6-methylguanine-[DNA methyltransferase](https://www.edgepedia.org/dna-methyltransferase) removes the lesion when it is base paired to T as well as to C in double-stranded DNA, that the lesion is less subject to repair in single-stranded DNA than previously reported, and that it may escape repair at the 3' terminus.[5](https://doi.org/10.1093/carcin/5.12.1733)
**Nonuniform mutation and repair.** A 1986 *Journal of Biological Chemistry* analysis of 151 O6-methyl-dGTP-induced mutations after passage through *E. coli* found significantly more unmutated mutation sites than expected, while mutated sites fit a [Poisson distribution](https://www.edgepedia.org/poisson-distribution); repair of O6-methylguanine lesions varied at least 3–4-fold with the position of the lesion.[9](https://doi.org/10.1016/s0021-9258(18)67598-2) The consensus sequence surrounding unmutated sites resembled the region of the rat Harvey ras oncogene containing the N-methyl-N-nitrosourea activation site for transformation, leading to the proposal that alkylation within such a sequence produces a DNA conformation less subject to repair.[9](https://doi.org/10.1016/s0021-9258(18)67598-2)
## References
1. Michael David Topal (born 1945), American biochemistry educator. Prabook. https://prabook.com/web/michael_david.topal/71310
2. Complementary base pairing and the origin of substitution mutations. *Nature*, 1976. https://doi.org/10.1038/263285a0
3. DNA precursors in chemical mutagenesis: a novel application of DNA sequencing. *Nature*, 1982. https://doi.org/10.1038/298863a0
4. Mechanism of mutagenesis by O6-methylguanine. *Nature*, 1984. https://doi.org/10.1038/308201a0
5. O6-Methylguanine-DNA transmethylase converts O6-methylguanine thymine base pairs to guanine thymine base pairs in DNA. *Carcinogenesis*, 1984. https://doi.org/10.1093/carcin/5.12.1733
6. DNA precursor pool: a significant target for N-methyl-N-nitrosourea in C3H/10T1/2 clone 8 cells. *PNAS*, 1982. https://www.pnas.org/doi/abs/10.1073/pnas.79.7.2211
7. DNA repair, oncogenes and carcinogenesis. *Carcinogenesis*, 1988. https://doi.org/10.1093/carcin/9.5.691
8. Mechanisms of chemical mutagenesis and carcinogenesis: effects on DNA replication of methylation at the O6-guanine position of dGTP. *Carcinogenesis*, 1983. https://doi.org/10.1093/carcin/4.12.1591
9. https://doi.org/10.1016/s0021-9258(18)67598-2
10. MGMT: A Personal Perspective. *Mutation Research*, 2009. https://pmc.ncbi.nlm.nih.gov/articles/PMC2692271/
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*Topic: Encyclopedia › Life and health › Life and health scientists › Life scientists › Researchers in genetics, genomics, and genome engineering › Mutagenesis and mutation research*
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