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Profile of Aziz Sancar hen biochemist Aziz San- become a research biochemist. When he car started his doctoral discussed his desire to pursue a Ph.D. studies in molecular biol- with his professor, how- ogy at the University of ever, Sancar was advised to practice TexasW at Dallas (Dallas, TX), he knew medicine, at least for a little while. In he faced an uphill battle. Trained as a the opinion of his professor, ‘‘anyone physician in , which at that time who gets a medical degree and gets all did not have the resources for rigorous this training should practice for a couple training in research science, Sancar of years before going into the basic sci- came to the United States believing he ences,’’ says Sancar. Even though he had would not be as skilled at the laboratory already made up his mind, he followed bench as other students. ‘‘To com- the advice and spent two rewarding pensate for this deficiency,’’ he says, years as a rural physician near his ‘‘I worked very hard and designed hometown of Savur. technically simple experiments that After concluding his medical practice would go to the heart of the problem.’’ in 1971, Sancar hoped to continue his When one of his early, ‘‘simple’’ ex- biochemistry training in the United periments repeatedly failed, Sancar be- States, a desire somewhat paralleled by gan to lose confidence in some of his a famous foreigner. ‘‘I recall around the abilities. One day the situation worsened time I arrived, John Lennon was also to the point where his benchmate told trying to come to the U.S., and the INS him, ‘‘Aziz, you have no talent for ex- would not allow him in because he had perimental research. I understand you a conviction for marijuana use,’’ Sancar were a good medical doctor; why don’t Aziz Sancar says. ‘‘When Lennon was asked why he you go back to practicing medicine?’’ was so determined to come to the Nevertheless, Sancar persisted, and his States, he said something like if he’d efforts have been successful, as evi- played hard on the soccer field. During lived during the time of the Roman denced by his 30-year research career his senior year of high school, Sancar, Empire, he would want to go to Rome covering DNA repair, check- who played goalkeeper, was invited to because that’s where the action was, points, and the . His attend tryouts for Turkey’s national un- and at the time the action was in the longest-running study has involved pho- der-18 soccer team. ‘‘This was a dream United States.’’ tolyase and the mechanisms of photore- come true because, since the age of 7, I In Sancar’s case, he had become in- activation. In his Inaugural Article in had wanted to play for the national terested in the phenomenon of photore- this issue of PNAS, Sancar captures the team,’’ he says. ‘‘However, upon serious activation, whereby DNA damage elusive radicals he has consideration, I decided I wasn’t tall caused by UV light can be repaired by chased for nearly 20 years, thus provid- enough to be an outstanding goalie, and longer-wavelength blue light. This reac- ing direct observation of the photocycle instead I concentrated on my studies.’’ tion is mediated by the enzyme photol- for thymine dimer repair (1). yase, which was identified years earlier Currently Sarah Graham Kenan Pro- by Claud Rupert at Johns Hopkins Uni- fessor of Biochemistry at the University ‘‘What we lacked versity (Baltimore, MD). At the time, in of North Carolina School of Medicine 1973, Rupert was teaching at the Uni- (Chapel Hill, NC), Sancar has employed with resources, versity of Texas at Dallas, and Sancar a strategy of hard work, perseverance, joined his laboratory and the university’s and technical simplicity in his science. we made up program. His honors include the Presidential A Scientist, a Technician, a Wordsmith Young Investigator Award from the Na- with enthusiasm.’’ tional Science Foundation (1984) and Rupert was an ideal advisor for Sancar. the highest awards from the American ‘‘He understood my capabilities and lim- Society for Photobiology (1990) and the Sancar excelled in many scientific dis- itations,’’ says Sancar. ‘‘He encouraged Turkish Scientific Research Council ciplines in high school, and, after gradu- me, gave me advice, and pointed me in (1995). Sancar, the first Turkish-Ameri- ating, he narrowed his career choices to the right direction. But, most impor- can member of the National Academy chemistry or medicine. He scored high tantly, he gave me the freedom to de- of Sciences, as well as its first University enough on his university entrance exam- velop my own ideas and test them. As of Texas at Dallas alumnus, was elected inations to attend the school of his both a scientist and a gentleman, he has in 2005. choice in Turkey, and he entered Istan- been the most influential person in my bul Medical School (Istanbul, Turkey) in career.’’ Goal Keeping 1963. Sancar remembers how his basic When Sancar joined Rupert’s group, Sancar was born the seventh of eight science professors conveyed the excite- the major question regarding photolyase children in 1946 in the small town of ment of scientific discovery extremely was the nature of its chromophore, a Savur in southeast Turkey. ‘‘My parents well. ‘‘What we lacked with resources, question Sancar became obsessed with were both illiterate,’’ he says, ‘‘but they we made up with enthusiasm,’’ he says.

valued the importance of education and After taking a biochemistry class dur- This is a Profile of a recently elected member of the National did their best to ensure that all of their ing his second year of the six-year pro- Academy of Sciences to accompany the member’s Inaugural children would receive some education.’’ gram and becoming highly interested in Article on page 16128. Sancar studied hard in school and the concepts learned, Sancar decided to © 2005 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0507558102 PNAS ͉ November 8, 2005 ͉ vol. 102 ͉ no. 45 ͉ 16125–16127 Downloaded by guest on September 25, 2021 ‘‘Yale was one of, if not the, center for DNA repair.’’ Feeding off this exciting environment, Sancar identified and cloned several E. coli repair genes within two years, in- cluding the uvrA, uvrB, and uvrC genes involved in excision repair (4–6). Armed with his newly cloned genes, Sancar purified the three Uvr proteins and re- constructed the mechanism of excision repair. To Sancar’s surprise, the com- plex did not just nick the DNA near the damage, which was a popular working model at the time, but instead made a cut on each side to excise a chunk of DNA (7). Sancar termed the enzyme for this activity excision nuclease, or exc- inuclease. With Rupp’s help, Sancar also invented a method for identifying plas- mid-encoded proteins through bacterial E. coli photolyase crystal structure. cells called maxicells (8). These maxi- cells were critical to his success in puri- fying the Uvr proteins. Within days of answering. ‘‘I told a fellow graduate stu- protein as well, but Rupert told him he publishing his paper on maxicells in the dent that I was willing to give my right had done enough to write his Ph.D. dis- Journal of Bacteriology in 1979, Sancar arm to identify the chromophore, and I sertation and graduate. received more than 100 letters request- meant it!’’ says Sancar. Before taking such Although graduating was fairly simple, ing his new cells, and he joyfully plas- drastic steps, however, he tried an experi- moving on proved difficult. Sancar had tered these letters all over Rupp’s office. mental approach to the problem. ‘‘About hoped to continue studying DNA repair, To this day, Sancar’s maxicell paper re- the time I started my research, recombi- but all three laboratories he applied to mains his most cited. Besides advancing nant DNA was born, and I realized I rejected him. Sancar’s fiance´e, fellow science, these two studies secured the could use this technology to overproduce graduate student Gwendolyn Boles, had terms ‘‘excinuclease’’ and ‘‘maxicell’’ as photolyase and identify the chromo- entries in the Oxford Dictionary of phore,’’ he says. ‘‘All I had to do was Biochemistry and Molecular Biology. clone the gene into a multicopy plasmid. ‘‘While trying to prove However, to do that, I first needed an Return to Photolyase E. coli mutant lacking photolyase.’’ was a In 1982, Sancar received an offer to join Sancar devised a conceptually simple the faculty at the University of North method to isolate photolyase-deficient photoreceptor, we Carolina (Chapel Hill, NC) as an Asso- mutants, which involved damaging bac- ciate Professor of Biochemistry. By that terial cells with germinated UV light ended up proving it time, his mentor, Rupert, had left re- and then restoring them with normal search to become the Dean of Arts and light. He notes that the method was sim- was an essential Sciences of the University of Texas at pler in concept than in execution, be- Dallas, and his departure allowed San- cause it did not work on the first, component of the car to resume his work on photolyase. second, or third try. Sancar persisted, Sancar joined the University of North and, 11 months after his first attempt, circadian clock itself.’’ Carolina, and, together with Boles and he managed to isolate a photolyase- other collaborators, he identified the Ϫ deficient phr mutant strain (2). He photolyase’s long sought-after chro- considers that experiment the one that secured a position in New York. ‘‘Fortu- mophore—both of them, in fact (9–11). truly made him a scientist. ‘‘It rein- ‘‘I was expecting one, and I found two,’’ nately, I learned that Dean Rupp at Ϫ forced my conviction that I had the abil- Yale was interested in cloning repair Sancar says. ‘‘One is FADH , and the ity to gather disparate facts from several genes, so I contacted him,’’ says Sancar. other is a pterin.’’ Sancar developed a fields to create a hypothesis, enough Although Rupp did not have a postdoc- model for the reaction mechanism of technical ability to carry out the experi- toral position available, he had a techni- photolyase repair (12–14) but had diffi- ments, and the perseverance to continue culty proving his scheme because he cian vacancy, and Sancar was hired, in the face of adversity,’’ he says. could not experimentally capture the nominally, as a technician in 1977. After that breakthrough, Sancar pro- proposed radical intermediates. ‘‘I ceeded to clone the photolyase gene in Like Rupert, Rupp proved a valuable worked with ultrafast spectroscopists in the spring of 1976 (3). ‘‘I believe it was mentor who further contributed to San- three different continents,’’ he says. the first gene to be cloned east of the car’s growth as a researcher. As in Dal- ‘‘Wherever there was an ultrafast lab in Rockies,’’ he says wryly. ‘‘At least that’s las, Sancar had managed to land in the the world, I found it.’’ what I tell my students to impress them.’’ middle of the action. ‘‘Besides Rupp, Sancar continued studying other DNA After a four-month return to Turkey to Yale had other pioneers of DNA repair repair pathways. Having answered some perform compulsory military service, Sec- such as Paul Howard-Flanders, who key questions about excision repair in ond Lieutenant Sancar returned to Texas helped discover excision repair and re- E. coli, Sancar turned his attention to to finish characterizing the cloned photol- combinational repair, Frank Hutchinson, excision repair in humans. Using a strat- yase gene. He had hoped to purify the and Charles Radding,’’ says Sancar. egy that took nearly five years to work

16126 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0507558102 Zagorski Downloaded by guest on September 25, 2021 out, Sancar showed in 1992 that humans example, E. coli has it, but Bacillus sub- circadian clock itself,’’ he says. ‘‘This dis- excise thymine dimers by the same mecha- tilis does not. At the mammalian level, covery was one of the most exciting things nism as E. coli (15). ‘‘This finding was marsupials have photolyase, but placen- that happened to me, since it opened up especially significant since, unlike all other tal mammals, like humans, do not.’’ Two an entirely new field to work on.’’ His repair mechanisms, the genes for excision years earlier, Sancar and his group per- continued studies with cryptochrome re- repair are not conserved between E. coli formed sensitive biochemical assays of vealed that this field was actually related and humans, indicating this is a conver- cells from several organisms to try to to other areas Sancar worked on. ‘‘I no gent mechanism,’’ he says. With the help detect photolyase but were unable to longer have three separate projects look- of an in vitro system developed by his find it in human samples (17). ‘‘So when ing at circadian clocks, cell cycle check- postdoctoral fellow, Christopher Selby, this EST came out, I said to the post- points, and DNA repair,’’ he says, ‘‘but rather I am shifting to having one big Sancar also managed to uncover the mo- docs who were involved in the biochemi- project that looks at the interconnected- lecular mechanism behind the phenome- cal work, ‘Well, maybe we made a ness of all three areas.’’ non of transcription-coupled repair, mistake, we’d better take a look at As new research avenues open up to whereby transcribed DNA is repaired at a this,’’’ Sancar recalls. Sancar, he has closed one chapter of his faster rate than nontranscribed DNA (16). In collaboration with HGS, Sancar’s research with the publication of his ‘‘I consider this paper one of the most laboratory identified a second human PNAS Inaugural Article, explaining the aesthetically pleasing ones of my career,’’ photolyase ortholog as an EST. The photolyase photocycle (1). Nearly 20 says Sancar. ‘‘It employed both classic and next step entailed elucidating the func- years after he first proposed the reac- modern methods, the data are unambi- tions of these two orthologs. ‘‘Humans tion mechanism for photolyase, instru- quous and of high quality, and every use light for two things, seeing in three mentation has improved to a point experiment worked as predicted by the dimensions and setting their biological where the mechanism can be demon- hypothesis.’’ clock,’’ says Sancar. Because the recep- strated. Along with Dongping Zhong tors involved in sight were well under- and colleagues at Ohio State University Circadian Clock Watching stood, Sancar suspected that these genes (Columbus, OH), Sancar captured the In 1995, the biotechnology company worked as circadian photoreceptors. He excited flavin intermediate and ob- Human Genome Sciences (HGS, Rock- named them 1 and 2 and served the photolyase photocycle, which ville, MD) released a set of human generated knockout mice to test his hy- involves electron transfer from the fla- expressed sequence tags (ESTs) that pothesis. Eliminating either gene pro- vin to the thymine dimer in 170 ps and included an entry for a photolyase or- duced circadian clock abnormalities, then back again from the repaired thy- tholog. This sequence proved a bit dis- whereas eliminating both completely mine in 560 ps. With his eye on the cir- concerting to Sancar, because, as far as abolished the clock (18). cadian clock, Sancar says, ‘‘These results he knew, humans did not possess pho- ‘‘While trying to prove cryptochrome represent a partial closing of my 33-year journey on photolyase.’’ tolyase. ‘‘Photolyase has an unusual evo- was a photoreceptor, we ended up prov- lutionary distribution,’’ he says. ‘‘For ing it was an essential component of the Nick Zagorski, Science Writer

1. Kao, Y.-T., Saxena, C., Wang, L., Sancar, A. & 7. Sancar, A. & Rupp, W. D. (1983) Cell 33, 249–260. 14. Sancar, G. B., Jorns, M. S., Payne, G., Fluke, D. J., Zhong, D. (2005) Proc. Natl. Acad. Sci. USA 102, 8. Sancar, A., Hack, A. M. & Rupp, W. D. (1979) J. Rupert, C. S. & Sancar, A. (1987) J. Biol. Chem. 16128–16132. Bacteriol. 138, 692–693. 262, 492–498. 2. Sancar, A. & Rupert, C. S. (1979) J. Bacteriol. 138, 9. Sancar, A. & Sancar, G. B. (1984) J. Mol. Biol. 172, 15. Huang, J. C., Svoboda, D. L., Reardon, J. T. & 779–782. 223–227. Sancar, A. (1992) Proc. Natl. Acad. Sci. USA 89, 3. Sancar, A. & Rupert, C. S. (1978) Gene 4, 294– 10. Jorns, M. S., Sancar, G. B. & Sancar, A. (1984) 3664–3668. 308. Biochemistry 23, 2673–2679. 16. Selby, C. P. & Sancar, A. (1993) Science 260, 4. Sancar, A., Wharton, R., Seltzer, S., Kacinski, B., 11. Johnson, J. L., Hamm-Alvarez, S., Payne, G., 53–58. Clarke, N. & Rupp, W. D. (1981) J. Mol. Biol. 148, Sancar, G. B., Rajagopalan, K.V. & Sancar, A. 17. Li, Y. F., Kim, S.-T. & Sancar, A. (1993) Proc. 45–62. (1988) Proc. Natl. Acad. Sci. USA 85, 2046–2050. Natl. Acad. Sci. USA 90, 4389–4393. 5. Sancar, A., Clarke, N., Griswold, J., Kennedy, W. 12. Sancar, G. B., Smith, F. W., Reid, R., Payne, G., 18. Thresher, R. J., Vitaterna, M. H., Miyamoto, Y., & Rupp, W. D. (1981) J. Mol. Biol. 148, 63–76. Levy, M. & Sancar, A. (1987) J. Biol. Chem. 262, Kazantsev, A., Hsu, D. S., Petit, C., Selby, 6. Sancar, A., Kacinski, B. M., Mott, L. & Rupp, 478–485. C. P., Dawut, L., Smithies, O., Takahashi, W. D. (1981) Proc. Natl. Acad. Sci. USA 78, 13. Jorns, M. S., Baldwin, E. T., Sancar, G. B. & J. S. & Sancar, A. (1998) Science 282, 1490– 5450–5454. Sancar, A. (1987) J. Biol. Chem. 262, 486–491. 1494.

Zagorski PNAS ͉ November 8, 2005 ͉ vol. 102 ͉ no. 45 ͉ 16127 Downloaded by guest on September 25, 2021