Volume 85 Issue 6 | p. 32 | Awards
Issue Date: February 5, 2007

Nobel Laureate Signature Award for Graduate Education in Chemistry

Department: ACS News
Banerjee
Credit: Sujata Bardhan
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Banerjee
Credit: Sujata Bardhan
Verdine
Credit: Harvard U
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Verdine
Credit: Harvard U

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We all dream of making a difference, and Anirban Banerjee appears to be living that dream. His Ph.D. mentor at Harvard University, chemistry professor Gregory L. Verdine, is quick to admit that Banerjee's graduate work has changed the course of his own lab's work. What's more, Banerjee's pioneering protein function experiments "have transformed the field of DNA repair, providing detailed new insights into how these proteins search for damage" in the genome, Verdine says.

Banerjee, now a postdoc at Rockefeller University, in New York City, is less brazen in describing his achievements, but his passion for the subject is clear. "Repair enzymes locate and excise damaged DNA nucleobases embedded in a greater than 1 million-fold excess of undamaged DNA," he explains. "It's one of the most formidable needle-in-a-haystack challenges in biology."

Verdine challenged Banerjee to work out a strategy for using a chemical cross-link to catch these enzymes in the act of searching the haystack, and Banerjee was immediately hooked. "At the time, most of my lab felt it could not be done," Verdine points out. But Banerjee was not so easily discouraged. He persevered and eventually developed a powerful cross-linking system that made it possible to crystallize otherwise uncrystallizable complexes of DNA repair proteins bound to short stretches of DNA.

In his cross-linking system, thiol groups are strategically installed on both the protein and the DNA substrate. They are then tethered via a disulfide bond. In this way, Banerjee was able to isolate normally fleeting protein-DNA complexes.

Until Banerjee developed his cross-linking system, the Verdine lab had repeatedly been unsuccessful in crystallizing the bacterial enzyme charged with preventing 8-oxoguanine from causing dangerous DNA mutations. With Banerjee's clever cross-linking strategy, however, the team captured a structure that shows how this enzyme recognizes that an adenine base has been mistakenly paired opposite an 8-oxoguanine (Nature 2004, 427, 652).

The same strategy has proven invaluable to probing how DNA repair enzymes search normal DNA for damage. For example, Banerjee used it to reveal that a related bacterial DNA repair enzyme uses a hydrophobic probe residue to examine the intact DNA helix for 8-oxoguanine (Science 2006, 311, 1068). When the enzyme encounters an 8-oxoguanine, it must flip the base out of the DNA helix and into its active site in order to remove it. Banerjee also used the cross-linking method to figure out how the human version of this enzyme ensures that only 8-oxoguanine is flipped into the active site and removed (Nature 2005, 434, 612). The enzyme first flips bases into a gatekeeper pocket that regulates entry to the active site, allowing any undamaged guanines that enter to return to the helix unharmed.

Banerjee, 32, who was born in India and earned a B.Sc. from Jadavpur University, in Calcutta, and an M.Sc. from the Indian Institute of Technology, Kanpur, left the Verdine lab with a Ph.D. in 2005. But the impact of his work is still apparent: Verdine estimates nearly half of the projects in his lab now rely on Banerjee's disulfide cross-linking strategy.

"It's rather rare that a graduate student transforms the research being done by the group of his or her Ph.D. supervisor," comments Jeremy R. Knowles of Harvard.

Banerjee is enthusiastic about the broad utility of the disulfide cross-linking strategy in mechanistic crystallography. As a Damon Runyon Cancer Research Foundation postdoctoral fellow in Roderick MacKinnon's lab at Rockefeller, Banerjee now is trying to exploit similar chemical strategies to capture mechanistically revealing snapshots of voltage-gated ion channels.

Verdine, whose lab studies the biochemical processes underlying the control of gene expression and the preservation of genomic integrity, received a B.S in chemistry from St. Joseph's University, in Philadelphia, and a Ph.D. in organic chemistry from Columbia University. After completing a postdoc at Harvard Medical School, he joined the faculty at Harvard University in 1988, where he has remained ever since. Among the many awards and honors he has received are ACS's Arthur C. Cope Scholar award and the Royal Society of Chemistry's Nucleic Acids Award.

The award address will be presented before the Division of Organic Chemistry.

 

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