DNA repair and cancer: the semicentennial.

Abstract

The FASEB JournalVolume 32, Issue 12 p. 6355-6355 EditorialFree Access DNA repair and cancer: the semicentennial First published: 05 November 2018 https://doi.org/10.1096/fj.181201ufmCitations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat “Where the rivers change direction, across the great divide” The 1950s saw the establishment of “DNA constancy,” in which measurements of the DNA of somatic cells in a given organism revealed very similar contents, and such measurements on germ cells revealed half as much. The revelation of DNA constancy played a tremendous heuristic role in the growing acceptance of DNA as the gene. In addition, and this took longer to be absorbed, the fact that the somatic cells of an organism have the same DNA content gave rise to the variable gene theory of differentiation and development, in which it is not the selective deletion or retention of genes but rather the varying patterns of their expression from a constant keyboard. But even prior to this period, DNA mutation had been discovered, and so DNA constancy, although hugely important, was nonetheless something of a misnomer: DNA was constant only if not changed. The induction of damage without repair (repair being unanticipated) was why Hermann J. Muller's X-irradiation experiments resulted in phenotypic change and was why the experiments of Beadle and Tatum in Neurospora were successful (leading to the principle of “one gene, one enzyme”), and why the acridine dye-induced frameshift mutations, uncorrected, allowed Sydney Brenner and Francis Crick and colleagues to deduce that the genetic code was a triplet nucleotide language. The notion that DNA damage can sometimes be repaired seems obvious in hindsight, but like all concepts in biologic science, it had to earn its wings. It was first seen in bacteria and later in mammalian cells. Discoveries in DNA repair were recognized by the 2015 Nobel Prize in Chemistry. Although not viewed as a parallel epistemological corridor at the time of the aforementioned mutagenesis-based discoveries, the question of cancer-causing genes subsequently arose. This concept was launched by Peyton Rous for a chicken sarcoma and then steadily rose, culminating in the discovery of viral genes that had been incorporated into the human genome. The notion that endogenous genes could undergo mutation into oncogenes was the key conceptual advance. But another essential concept had already been well established—a link between deficiencies in DNA repair and cancer. This discovery preceded the oncogene era, and this year is its 50th anniversary. A connection between UV sensitivity and skin cancer had long been known, but in 1967, a young research fellow at the University of California, San Francisco, James Cleaver (Fig. 1), had the idea that the reason patients with the UV-sensitive disease xeroderma pigmentosum (XP) had an elevated incidence of skin cancer was perhaps because they could not repair the DNA lesions. This was a bold conceptual leap, viz.,that a defect in DNA repair could be carcinogenic. In short order, Cleaver demonstrated that cells from patients with XP were indeed defective in DNA repair (1, 2). This milestone paper generated further discoveries that solidified the connection between DNA repair deficiencies and many human cancers. Deficiencies in DNA repair are now known to lie at the pathogenesis of many human diseases beyond cancer. At the 50th anniversary of his seminal paper, let us take this opportunity to salute James Cleaver for his keen nose and all that it has meant for the modern era of the field of DNA repair and cancer. Figure 1Open in figure viewer James Cleaver. Epilogue: The quoted line is by the American songwriter Kate Wolf (1942–1986), who penned it as a metaphor for changing one's world view, just as ideas about genes and cancer eventually also changed, not across the western orogenic mountain range of the North American continent, but from a century of oppositional views. REFERENCES 1Cleaver, J. E. (1968) Defective repair replication of DNA in xeroderma pigmentosum. Nature 218, 652– 656 2Wood, R. D. (2018) Fifty years since DNA repair was linked to cancer. Nature 557, 648– 649 Citing Literature Volume32, Issue12September 2018Pages 6355-6355 FiguresReferencesRelatedInformation