Researchers from the University of Colorado-Denver and Health Sciences Center and Stanford University have discovered a molecular mechanism that explains how cells respond to DNA damage and other acute stresses, and if disrupted can cause cancer. Their findings, which could lead to new diagnostic markers and cancer treatments with fewer side effects, will appear in two reports in the May 21 advanced online version of the journal Nature.
The studies, led by Tatiana Kutateladze, PhD, an assistant professor in the UCDHSC Department of Pharmacology, and Or Gozani, MD, PhD, an assistant professor in the Department of Biological Sciences at Stanford University, revealed the significance of a novel function of the recently discovered tumor-suppressive molecule, which is thought to inhibit cancer formation and growth. These findings highlight a new mechanism to regulate gene expression programs that allow for appropriate responses to DNA damage in normal cells. When the process breaks down, such damage and other acute stresses are thought to lead to cancer.
The first study, Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2, was conducted in Kutateladze’s laboratory with the assistance of graduate student Pedro Peña and research assistant Foteini Davrazou. Other co-authors include Rui Zhao, PhD, an assistant professor in the UCDHSC Department of Biochemistry and Molecular Genetics; Or Gozani, Xiaobing Shi and Kay L. Walter from Stanford University’s Department of Biological Sciences; and Vladislav V. Verkhusha from the Department of Anatomy and Structural Biology at the Albert Einstein College of Medicine in New York.
The paper based on their work describes the structural aspects of the tumor suppressor action, while functional studies were accomplished by Gozani’s group, and are the subject of the second report that will appear in Nature titled ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression.
"Our findings have established the mechanistic principles by which the inhibitor of growth 2 tumor suppressor recognizes chromatin and regulates cell growth, proliferation, stress responses and aging. We hope this discovery opens up new opportunities to establish novel targets to prevent and treat cancer," said Kutateladze, a NARSAD Young Investigator and an American Cancer Society Research Scholar.
Research in Kutateladze’s laboratory focuses on molecular mechanisms underlying signaling and regulation by chromatin- and lipid-binding biomolecules implicated in cancer and other human diseases. She employs high field Nuclear Magnetic Resonance spectroscopy, X-ray crystallography and other biochemical and biophysical approaches to elucidate three-dimensional atomic-resolution structures and dynamics of proteins to better understand their physiological functions and relevance to diseases.
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