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Sunlight damages the DNA in your skin cells every day. Most of that damage is fixed before it causes harm, because cells carry repair kits. Aziz Sancar worked out, molecule by molecule, how one of the most important kits works. This post covers his unusual path into science, what he discovered, and the simple arithmetic at the heart of it.
Who is Aziz Sancar?
His Nobel facts page records that he was born on 8 September 1946 in Savur, in south-east Turkey, to parents with no formal education who valued it for their children. In his Nobel autobiography he writes that he was the seventh of eight children of a farming family, that his mother, who could not read or write, insisted that all her children be educated, and that his oldest brother taught him to read when he was five.
He studied medicine at Istanbul University and, after graduating at the top of his class, practised medicine around Savur. He recalls those 18 months as the happiest time of his life, but also intellectually frustrating: he wanted to know, for example, why streptomycin killed the tuberculosis bacterium but penicillin did not. That question pulled him towards biochemistry.
What question started his research?
The Nobel Committee's popular science background describes the puzzle that caught him: bacteria exposed to deadly doses of ultraviolet (UV) light could recover if they were then illuminated with visible blue light. He joined Claud Rupert's laboratory at the University of Texas at Dallas, where, the Nobel Committee notes, he cloned the gene for the enzyme behind this, photolyase, in 1976.
The work earned him a doctorate, but three applications for postdoctoral positions were rejected. To keep working on DNA repair he took a job as a laboratory technician at Yale University School of Medicine, in the group of W. Dean Rupp. In his autobiography he names three qualities a scientist needs: "creativity based upon knowledge, hard work, and perseverance in the face of failure."
How does nucleotide excision repair work?
UV light can link two neighbouring thymine bases on the same strand, forming a thymine dimer. The Nobel Committee's scientific background explains that such lesions interfere with normal base pairing and distort the double helix. Bacteria repair this damage in the dark as well as with light, and the dark system depended on three genes, uvrA, uvrB and uvrC.
At Yale, Sancar isolated the proteins made by these genes and put the repair reaction together in a test tube. His autobiography describes the surprise of spring 1982: the UvrABC enzyme made two cuts, one 7 nucleotides on the 5′ side of the dimer and one 3 to 4 nucleotides on the 3′ side. He published it in Cell in 1983 with Rupp.
The scientific background describes the rest of the cut-and-patch process: a helicase (UvrD) removes the cut piece, DNA polymerase I fills the gap by copying the intact strand, and DNA ligase seals the backbone.
Worked example: how long is the cut-out piece?
Use the numbers from Sancar's bacterial experiments.
A thymine dimer is two adjacent nucleotides.
The 5′ cut is 7 nucleotides away from the dimer: count 7.
Add the dimer itself: 7 + 2 = 9.
The 3′ cut is 3 or 4 nucleotides beyond the dimer: 9 + 3 = 12, or 9 + 4 = 13.
So the excised fragment is 12 to 13 nucleotides long, exactly the figure the Nobel Committee gives. A common mistake is to forget the dimer's own two nucleotides and get 10 or 11.
In human cells the pieces are longer. Sancar's autobiography records that on 8 November 1991 his group caught the excised human fragment, about 27 nucleotides long, made by dual incisions. "There is an important biological fact about humans that is known only to God and me," he told his wife, Gwen. The scientific background adds that the human system needs more than fifteen proteins for damage recognition and dual incision, against three in E. coli.
To revise how the strands pair and copy, see our guides to DNA replication and transcription and point and frameshift mutations. If the vocabulary of 5′ and 3′ ends still feels shaky, the Fermi Concept Library covers every concept in physics, chemistry, biology, mathematics and computing, so you can revise the one idea that is blocking you.
Why does this repair system matter?
The 2015 Nobel press release shared the prize between Tomas Lindahl, Paul Modrich and Sancar "for mechanistic studies of DNA repair". It notes that people born with defects in nucleotide excision repair develop skin cancer if exposed to sunlight; the popular background names this condition xeroderma pigmentosum. Cells also use the same system to repair damage from mutagenic substances, such as those in cigarette smoke.
Sancar's career kept turning back to his first question. The popular background notes that he later worked out how photolyase revives bacteria, and helped show that a human relative of photolyase helps set the body's circadian clock.
What can a student take from how Sancar worked?
He left Johns Hopkins in 1972, partly because he could not yet communicate well in English, went home to regroup, and came back. In 1981, his autobiography says, he applied to about 50 universities for faculty jobs and was turned down by all of them until the University of North Carolina called. Rejection was part of the route, not the end of it.
Try it now: if a repair enzyme cut 5 nucleotides on one side of a dimer and 4 on the other, how long would the removed piece be? Check that you counted the dimer.
