New Study Discovers the Three-Dimensional Structure of the Genome Replication Machine
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
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report's Best Hospitals, receiving high "Honor Roll" status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children's Hospital among the country’s best in several pediatric specialties.