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Phil Hanawalt is a Professor of Biology and has been a leader in the field of DNA repair since his pioneering discovery of repair replication in E. coli in 1963. He also demonstrated repair replication in mycoplasmata and in a eukaryote (Tetrahymena) and he has developed a number of important experimental approaches for studying repair, beginning with the BrdUrd density labeling method for resolving semiconservatively replicated DNA from parental DNA containing repair patches. Hanawalt's approach was used by James Cleaver in 1968 to first document a DNA repair defect in xeroderma pigmentosum. The method was also used to validate the widely used phenomenon of unscheduled DNA synthesis as a measure of DNA repair.
Other significant research contributions from Hanawalt's laboratory have included: the demonstration of preferential mutagenesis by N-methyl nitrosoguanidine at DNA replication forks and its application to mapping genes; early evidence for membrane association of the DNA replication complex in E. coli and in mammalian cells; discovery of long-patch excision-repair in E. coli and the demonstration that it is an inducible component of the Rec A-Lex A regulatory circuit; discovery of a gene controlling nucleotide uptake in E. coli; development of permeabilized bacterial and mammalian cell systems to study excision-repair pathways; demonstration of enhanced survival of UV irradiated Simian Virus 40 upon treating the host cells with low doses of UV or chemical carcinogens; discovery that the T4 endonuclease V operates processively on damaged DNA; the discovery that certain types of damage in transfecting plasmid DNA markedly enhances the efficiency of stable transformation in human cells and the discovery that UV irradiation of short sequences of nucleotides can result in their ligation through pyrimidine dimerization, providing a plausible mechanism for prebiotic assembly of high molecular weight duplex DNA.
In 1982 Hanawalt and his colleagues reported the first example of intragenomic DNA repair heterogeneity: chemical adducts in alpha DNA in African green monkey kidney cells were not as efficiently repaired as in the genome overall. In 1983 Mansbridge and Hanawalt discovered that cells from xeroderma pigmentosum (group C) only repair limited genomic domains, now known to be expressed genes. Hanawalt and his colleagues then discovered that repair of some types of damage is selective; active genes are preferentially repaired, and in fact a special repair pathway termed transcription-coupled repair (TCR) operates on the transcribed strands of expressed genes. TCR was documented in mammalian cells, in E. coli, and in yeast chromosomal and plasmid borne genes. The discovery of TCR in Hanawalt's laboratory has had profound implications for the fields of mutagenesis, environmental carcinogenesis, and risk assessment.
Recent research is focused upon the effects of DNA lesions and unusual structures on transcription elongation by various RNA polymerases, with particular emphasis upon formation of transcription-dependent R-loops, and on the examination of responses to oxidative injury in cells from patients of the DNA repair deficient disorders xeroderma pigmentosum, Cockayne syndrome and UV-sensitive syndrome.