Nobel Prize Winners Emphasize Importance of DNA Repair
It has been a long time coming, to see the importance of DNA repair reach the Nobel committee. For those of us who know these three individuals well, myself, Nate Berger and Sandy Markowitz, it is a reaffirmation that understanding the fundamental biology of DNA repair is critical to disease and in particular to understanding cancer - its etiology, progression, and treatment - and for that matter, stem cells. For me, it is wonderful to see these individuals recognized, people that I've known my entire career, had lunch and dinner with, shared the podium with at small and international conferences, and cross-referenced each other's work.
Lindahl, Modrich and Sancar have defined the field of DNA damage and repair, and have provided fundamental approaches to unraveling the proteins involved in individual pathways, in providing an overall assessment of genome stability and it's importance in biology species and evolution. What was slowly uncovered, was that these pathways have been an almost constant in evolution, with most proteins already constituted in bacteria and yeast.
I first crossed paths with Tomas Lindahl in 1983 when Nate Berger asked me to work with David Goldthwait, then professor of Biochemistry here at CWRU, to understand the repair of O6-methylguanine. When Tomas described the methylation of guanine at the O6 position as remarkably mutagenic, and at the N7 position as cytotoxic, and later when he led to the identification of the methylguanine methyltransferase gene responsible for its repair, he broke open the fields of single nucleotide repair.
We exploited this by the discovery of O6-benzylguanine to block the human protein, and recognized that the bacterial counterpart was resistant due to a polymorphism at position 140. We then created the human P140KMGMT as a stem cell gene therapy approach to protect hematopoiesis from chemotherapy. This is now being tested in patients with glioma at two clinical trials here, led by Andy Sloan, and at Fred Hutchinson Cancer Research Center, led by Hans-Peter Kiem.
The second touch point is our study of the role of uracil DNA glycosylase, first described and purified by Tomas. His appreciation of the role of basic excision repair and its importance in toxicity led to our utilization of methoxyamine (licensed by CWRU to Tracon Pharmaceuticals as TRC102) as an agent to block base excision repair. Tests of this compound are taking place in three phase 2 clinical trials across the country.
Paul Modrich has the most exquisite understanding of mismatch repair of anyone in the world. One has the sense that he views DNA repair processes in four dimensions and sees DNA-protein interactions taking place in real time. Sandy Markowitz and I have worked with Paul on mismatch repair processes. My lab evaluated the role of loss of mismatch repair in methylating agent chemotherapy resistance due to the lack of recognition of O6-methylguanine by the mismatch repair complex, while Sandy has been interested in loss of mismatch repair-mediated colon cancer, both sporadic and hereditary.
Finally, Aziz Sancar has the most complex task, and that is explaining nucleotide excision repair, perhaps the most profound DNA repair pathway associated with human disease. It is also the most complex with over 26 genes and proteins involved and multiple lesions repaired. His interest began and has remained in understanding UV damage and repair, and he discovered many of the genes and proteins involved in nucleotide excision repair. The lesions repaired are intrastrand and interstrand DNA crosslinks and bulky DNA adducts, often creating complex DNA damage. These lesions must be repaired for replication, transcription and translation to occur. He helped to define the concept of transcription couple repair, the role of circadian rhythm in repair, as well as cycle cell cycle regulation of DNA repair protein expression, and the variance within tissues, skin in particular, in excision repair capacity.
Lindahl, Modrich and Sancar have one thing in common - the demand for precision in understanding the pathways and intermediates in these DNA repair processes. In these days of a preoccupation with targeted therapeutics, these three individuals remind us that the best target in cancer remains the DNA of tumor cells.