Richard B. Setlow, a commentary on seminal contributions and scientific controversies

Abstract

Richard B. Setlow inspired the field of DNA repair. His demonstration that photoproducts could be quantified within cells and their excision examined experimentally pioneered the identification of nucleotide excision repair. His early work was associated with the discovery of many founding phenomena of photobiology and DNA repair: the concept of excision repair itself, correlations between DNA repair, life span and aging, variations in repair among mammalian species, caffeine sensitization to UV damage, and the xeroderma pigmentosum (XP) repair deficiencies. We may now have mapped thoroughly the landscape of DNA repair that Dick helped open to exploration, but questions persist of how comprehensively we have explored all its canyons and mesas. Research into nontraditional species and kingdoms may yet provide unexpected surprises. The signal transduction pathways and mechanisms of DNA replication arrest in damaged mammalian cells remain a challenge. The importance of repair in vivo also provides many difficult research questions. One problem of current interest is the role of endogenous DNA damage and repair in human pathology, especially neurodegeneration exemplified by many XP patients. Cancer and neurodegeneration may represent converse responses of dividing and nondividing cells to mutagenic and lethal effects of DNA damaging agents. Cell death from endogenous oxidative DNA damage (apoptosis) may be antagonistic to malignant transformation in dividing cells but may cause neurodegeneration in nondividing neural tissue. Small reductions in the efficiency of repair, especially transcription-coupled repair, may overemphasize carcinogenesis in mice, while minimizing neurodegeneration, as compared to human patients.

Shaping Vulnerable Bodies at the Thin Boundary between Environment and Organism: Skin, DNA Repair, and a Genealogy of DNA Care Strategies

“…This is the story of xeroderma pigmentosum (XP), a rare skin disease. The tale begins with James Cleaver, a biophysicist who joined the Laboratory of Radiobiology at the University of California, San Francisco (UCSF), in 1966 to study irradiated rodent cell lines (for biographical notes see Cleaver 2001, 122–124; Cleaver 2005, 635–636). Cleaver was intrigued by mutation research, especially the latest reports that some one-celled bacteria were able to repair mutations induced by UV light.…”

“…Within a year, Cleaver and his colleagues revealed the secret of XP. “The first two papers, in Nature and PNAS , established the discovery” (Cleaver 2001, 123). Normal human skin cells behaved similarly to bacteria in that they could repair UV damage to the DNA, but the skin cells of XP patients lacked this capacity.…”

“…Cleaver remembers the implication of his discovery: “Unbeknownst to me at the time, we had demonstrated that human cancer could be a genetic disease to be understood in terms of damage and repair to human genes. XP, and cancer in general, might therefore yield to a molecular understanding” (Cleaver 2001, 123). The molecularization of mutagenesis and of the environmental effects on the organism made a difference in how the toxicology of mutagens and carcinogens was perceived.…”