The Nobel Prize in Chemistry 2015.
“for mechanistic studies of DNA repair”
Sancar was born in Turkey in 1946 and got his MD degree from the Faculty of Medicine of Istanbul University. He then went on to get a Ph.D. with Claud S. Rupert at the University of Texas at Dallas in 1977. The Rupert lab worked on DNA repair and Sancar's thesis topic was the photoreactivating enzyme in E. coli. The photoreactivating enzyme was an enzyme that repaired DNA damage.
Sancar eventually secured a position at the University of North Carolina, Chapel Hill where he worked on excision repair and on photoreactivation. He is best known for his study of the mechanism of photolyase, the enzyme that repairs thymine dimers. [see Monday's Molecule #242] Photolyases are present in bacteria, protozoa, fungi, plants, and most animals. The gene for photolyase has been lost in placental mammals.
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Nobel Laureates
Aziz Sancar’s fascination with life’s molecules developed while he was studying for a medical degree in Istanbul. After graduating, he worked for a few years as phycisian in the Turkish countryside, but in 1973 he decided to study biochemistry. His interest was piqued by one phenomenon in particular: when bacteria are exposed to deadly doses of UV radiation, they can suddenly recover if they are illuminated with visible blue light. Sancar was curious about this almost magical effect; how did it function chemically?Claud Rupert, an American, had studied this phenomenon and Aziz Sancar joined his laboratory at the University of Texas in Dallas, USA. In 1976, using that time’s blunt tools for molecular biology, he succeeded in cloning the gene for the enzyme that repairs UV-damaged DNA, photolyase, and also in getting bacteria to over-produce the enzyme. This work became a doctoral dissertation, but people were hardly impressed; three applications for postdoc positions resulted in as many rejections. His studies of photolyase had to be shelved. In order to continue working on DNA repair, Aziz Sancar took up a position as laboratory technician at the Yale University School of Medicine, a leading institution in the field. Here he started the work that would eventually result in the Nobel Prize in Chemistry.
By then it was clear that bacteria have two systems for repairing UV damage: in addition to light-dependent photolyase, a second system that functions in the dark had been discovered. Aziz Sancar’s new colleagues at Yale had studied this dark system since the mid-1960s, using three UV-sensitive strains of bacteria that carried three different genetic mutations: uvrA, uvrB and uvrC.
As in his previous studies of photolyase, Sancar began investigating the molecular machinery of the dark system. Within a few years he had managed to identify, isolate and characterise the enzymes coded by the genes uvrA, uvrB and uvrC. In ground-breaking in vitro experiments he showed that these enzymes can identify a UV-damage, then making two incisions in the DNA strand, one on each side of the damaged part. A fragment of 12-13 nucleotides, including the injury, is then removed.
Aziz Sancar’s ability to generate knowledge about the molecular details of the process changed the entire research field. He published his findings in 1983. His achievements led to an offer of an associate professorship in biochemistry at the University of North Carolina at Chapel Hill. There, and with the same precision, he mapped the next stages of nucleotide excision repair. In parallel with other researchers, including Tomas Lindahl, Sancar investigated nucleotide excision repair in humans. The molecular machinery that excises UV damage from human DNA is more complex than its bacterial counterpart but, in chemical terms, nucleotide excision repair functions similarly in all organisms.
So, what happened to Sancar’s initial interest in photolyase? Well, he eventually returned to this enzyme, uncovering the mechanism responsible for reviving the bacteria. In addition, he helped to demonstrate that a human equivalent to photolyase helps us set the circadian clock.
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