Repairing DNA after it breaks is a crucial part of how genomes maintain their stability from one generation to the next. When this repair mechanism breaks down, defects in DNA are passed on and sometimes lead to cancer.
A biophysical chemist now at The University of Texas at Austin is seeking to better understand how this repair mechanism works in order to find ways to exploit it to cure cancer. Ilya Finkelstein joined the faculty of the department of chemistry & biochemistry in 2012 with a First-Time Tenure-Track Award from CPRIT. He was recruited from Columbia University Medical Center, where he was a postdoctoral fellow.
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Repairing DNA after it breaks is a crucial part of how genomes maintain their stability from one generation to the next. When this repair mechanism breaks down, defects in DNA are passed on and sometimes lead to cancer.
A biophysical chemist now at The University of Texas at Austin is seeking to better understand how this repair mechanism works in order to find ways to exploit it to cure cancer. Ilya Finkelstein joined the faculty of the department of chemistry & biochemistry in 2012 with a First-Time Tenure-Track Award from CPRIT. He was recruited from Columbia University Medical Center, where he was a postdoctoral fellow.
While at Columbia, Finkelstein pioneered a technique that allowed him to visualize thousands of individual DNA molecules at the same time and watch the DNA-repair machinery at work under a microscope. This allows him to study fundamental questions of both the molecular basis of cancer and the therapeutic treatment of different cancer types.
“We capture the very intricate dance of these proteins on the DNA lesion that they are trying to repair,” Finkelstein says. It’s a molecular choreography that helps maintain the stability of the genome.
While mutations in this DNA-repair machinery can lead to cancer, a cancer cell is also unusually dependent on this same machinery to maintain its own genome. Cancer cells grow in very unhealthy conditions and are sensitive to things that damage their genome. Because of their outsize dependence on the repair machinery, that’s provided a target for some of the most important anti-cancer drugs so far developed.
Finkelstein’s lab is also helping to make new gene-editing tools safer. CRISPR Cas-9 is being used to cut genes out of a DNA sequence, which then allows the cell’s own genome-repair machinery to go to work.
One problem with CRISPR is that it is not perfect at recognizing DNA sequences; like a spell-checker that sometimes causes more misspellings than it corrects. Say a spell-checker recognizes that the word “THRUGH” is misspelled. But instead of correcting it to “THROUGH,” as the writer intended, it changes the word to “THOUGH.” Similar mistakes are possible with CRISPR. But misspellings can be worse than a headache, since unintended errors in a genome can cause cancer.
Finkelstein seeks to better harness a cell’s own repair mechanisms in such a way as to make gene editing safer and more accurate. Curing one disease by doing genome editing won’t be worth the cost, if in the end it leads to cancer, he says.
His interest in genome editing and DNA repair are two sides of the same coin, he says. “We like to live at the interface between break and repair.”
Finkelstein is grateful to CPRIT for giving him the opportunity to do cutting-edge basic cancer research in Texas .
“The real importance of CPRIT is that it nucleated an important DNA-repair research community,” Finkelstein says. “I do believe that you can’t translate the research to the bedside if you don’t first have basic research. There is no translation if you don’t understand the language to begin with.” He adds, “CPRIT is the Texas science miracle.”
Finkelstein received his undergraduate degree in chemistry from the University of California, Berkeley, and his Ph.D. in chemistry from Stanford University. He became a postdoctoral fellow in chemistry & molecular biophysics at Columbia University Medical Center in 2007.
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