Mount Sinai researchers have discovered how the enzyme DNA polymerase delta works to duplicate the genome that cells hand down from one generation to the next. In a study published in Nature Structural & Molecular Biology, the team also reported how certain mutations can modulate the activity of this enzyme, leading to cancers and other diseases.
"DNA polymerase delta serves as the duplicating machine for the millions to billions of base pairs in human and other genomes. We were able to present for the first time a near-atomic-resolution structure of the complete enzyme in the act of DNA synthesis," says lead investigator Aneel Aggarwal, PhD, Professor of Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai. "This knowledge furthers our basic understanding of this complex enzyme which is essential for survival in higher organisms from humans to yeast. At the same time, our work provides insights into how cancers can arise when DNA polymerase delta is not functioning properly, and offers a novel basis for designing inhibitors of the polymerase that could potentially serve as effective treatment in certain cancers."
While DNA polymerase delta has been studied by scientists for decades, many questions remain about its overall architecture and dynamics. "We showed how the various pieces of this complicated machine work synchronously with one another to copy the genome with amazing accuracy," explains Dr. Aggarwal. His team, which included co-author Rinku Jain, PhD, Assistant Professor of Pharmacological Sciences at the Icahn School of Medicine, also mapped a number of inherited mutations (which are passed down from parent to child) and somatic mutations (which occur by chance during someone's lifetime) in DNA polymerase delta that are associated with "hypermutated" tumors. In addition to cancers, these mutations may be associated with multi-symptom mandibular hypoplasia, deafness, and lipodystrophy syndrome.
Essential to the Mount Sinai researchers' work were recent advances in cryo-electron microscopy. This technology, which allows for the imaging of rapidly frozen molecules in solution, is revolutionizing the field of structural biology through its high-resolution pictures. This technique allowed Dr. Aggarwal and his team to examine not only individual atoms of the DNA polymerase delta but also how they move to achieve accurate replication of the genome. Integral to this phase of the research was Mount Sinai's partnership with the Simons Electron Microscopy Center in New York City.
Building on its latest groundbreaking work around DNA polymerase delta, Mount Sinai will continue to explore the unique structure and mechanism of the polymerase, particularly its relationship to cancer and disease pathogenesis. "We know that certain cancers become dependent on this enzyme for their survival," says Dr. Aggarwal, "and inhibiting its activity could provide a valuable therapeutic window for future medical research."
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest integrated delivery system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Gynecology, Nephrology, Neurology/Neurosurgery, and Orthopedics in the 2019-2020 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology and Mount Sinai South Nassau is ranked 35th nationally for Urology. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and Mount Sinai South Nassau are ranked regionally.
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