The genetic material in human cells breaks all the time, and nearly always, this damage is repaired before it causes further problems. But how that repair happens in normal cells, and how it goes awry and causes cancer, are questions that are not fully understood.
Now a professor at the University of Texas Southwestern Medical Center is using cutting-edge microscopy to investigate the inner workings of cells to study DNA repair in fine detail. Daniela Nicastro was recruited from Brandeis University, with the help of a CPRIT Rising Star Award, to join the department s of cell biology and biophysics.
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The genetic material in human cells breaks all the time, and nearly always, this damage is repaired before it causes further problems. But how that repair happens in normal cells, and how it goes awry and causes cancer, are questions that are not fully understood.
Now a professor at the University of Texas Southwestern Medical Center is using cutting-edge microscopy to investigate the inner workings of cells to study DNA repair in fine detail. Daniela Nicastro was recruited from Brandeis University, with the help of a CPRIT Rising Star Award, to join the department s of cell biology and biophysics.
She studies the structure and sub-cellular organization of important components of the cell nucleus, in order to better understand the molecular and cellular basis of cancer.
Nicastro rapidly freezes cells to get ice-crystal–free frozen samples. Then she use s a technique she developed to essentially “sand blast” the frozen cell with an ion beam until only a thin slice is left. Her goal is to have a section of the “heart” of the cell thin enough to “see” through using a beam of electrons.
She then uses cryo-electron microscopy and tomography to visualize the three-dimensional structure of a cell to better understand its inner workings. In some ways, it’s similar to light microscopy but allows her to see nano-machines inside the nucleus of the cell in much, much finer detail, and create a three-dimensional reconstruction.
“There are millions of questions that we could ask,” using this technique, she says. “But I want to go to the nucleus, the heart of the cell, where almost everything has to do with DNA. That screams cancer relevance.”
She had the idea for using the cryogenic cellular milling technique many years ago, but it took coming to UT Southwestern, and the resources provided by the CPRIT grant, for her to obtain the instruments she needed. Only two or three other instruments of this kind exist in the U.S.
Her knowledge and skills bridge the structural biology and light microscopy strengths already at UT Southwestern.
In addition to studying DNA repair, one of the other questions Nicastro is trying to answer is how cancer cells defeat the normal cellular aging process. In normal cells, every time a cell replicates, it ages. And eventually it dies. In a cancer cell, an enzyme called telomerase acts like the “Fountain of Youth,” helping the cell circumvent this aging process and keep reproducing. In cancer patients, eternally youthful cancer cells produce unchecked growth—a tumor.
“Could telomerase be a chemotherapy target?” Nicastro wonders. “Could we make the cancer cells senescent again?”
A third focus of her research is the structure and function of intracellular compartments, which self-organize into functional clusters without the membrane typical of cell organelles. Using cryo-EM, Nicastro can visualize these compartments in unprecedented detail.
She says her work is time-consuming, because not only is she investigating scientific questions of great interest in cancer research, but also at the same time she is developing the advanced microscopy and cell-slicing techniques. She also directs the cryo-EM core facility, which is available to the larger research community at UT Southwestern.
Nicastro received her undergraduate and Ph.D. degrees in biology from the Ludwig - Maximilians University in Munich, Germany. Prior to joining the faculty at Brandeis in 2006, she was a postdoctoral fellow at the University of Colorado, Boulder.
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