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New study reveals the structure of DNA helicase at the replication fork

January 16, 2017

GRAND RAPIDS, Mich. (Jan. 16, 2017)--Scientists at Van Andel Research Institute and Rockefeller University have successfully described a crucial structure involved in DNA replication, placing another piece in the puzzle of how life propagates.

The latest study from long-time collaborators Huilin Li, Ph.D., and Michael O'Donnell, Ph.D., published today in the Proceedings of the National Academy of Sciences, elucidates the interaction between DNA and the eukaryotic enzyme CMG helicase, which opens the DNA double helix like the slider of a zipper and prepares the genetic code for copying.

"Since discovery of the DNA double helix more than 50 years ago, helicase's activity in preparing DNA for replication has been poorly understood," says Li, professor at Van Andel Research Institute. "However, recent advances in microscopy and study design allow us to create accurate images of these enzymes and observe their interactions with DNA for the first time."

More than 40 diseases, including many cancers, anemias and ataxias, in addition to several rare and orphan disorders, trace their origins at least partially to inaccuracy or failures in DNA replication. Results of this study offer a schematic for a core driver behind DNA replication, which Li and O'Donnell hope will eventually help the development of new treatments for these diseases.

"Biologists have learned a great deal about the molecular structure and functions of the enzymes and proteins related to DNA replication," says O'Donnell, professor at Rockefeller University and Howard Hughes Medical Institute investigator. "However, we still have much to discover, and this understanding of helicase activity brings us another step closer."

Findings from the new study reverse a long-held assumption about the orientation of helicase around DNA. Images taken during DNA unwinding demonstrate that helicase's N-tier ring leads the C-tier motor ring and makes first contact with double-stranded DNA. Such orientation is opposite from the currently accepted polarity and has important implications in understanding the mechanism of replication.

Helicase activity has long been recognized as a critical part of DNA replication, itself a fundamental process in the propagation of life. With the publication of this study, scientists have a more complete picture of how most advanced life on Earth proliferates.

This study involved evaluation of CMG helicase purified from the baker's yeast Saccharomyces cerevisiae, an organism commonly used to model higher eukaryotes, including humans.

The structure of the helicase on DNA was derived at Rockefeller University's cryo-electron microscopy (cryo-EM) core facility, leveraging a groundbreaking imaging technology that has revolutionized scientists' ability to visualize and understand the role of fundamental biological processes.

With VARI's recent installation of its own world-class Cryo-EM Core, including the powerful Titan Krios, Li expects the pace of discovery and understanding of these basic biological processes will accelerate in Grand Rapids.
Study authors include Roxana Georgescu, Dan Zhang, Olga Yurieva, and Michael O'Donnell, all of Rockefeller University and Howard Hughes Medical Institute; Lin Bai and Huilin Li, of Van Andel Research Institute; Zuanning Yuan and Ruda de Luna Almeida Santos of Stony Brook University; and Jingchuan Sun, of University of Pennsylvania. Yuan and de Luna Almeida Santos also are affiliated with VARI.

Funding for the study came from Van Andel Research Institute, Howard Hughes Medical Institute and the National Institute of General Medical Sciences of the National Institutes of Health under Award Number GM111742. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

About Van Andel Institute

Van Andel Institute (VAI) is an independent nonprofit biomedical research and science education organization committed to improving the health and enhancing the lives of current and future generations. Established by Jay and Betty Van Andel in 1996 in Grand Rapids, Michigan, VAI has grown into a premier research and educational institution that supports the work of more than 360 scientists, educators and staff. Van Andel Research Institute (VARI), VAI's research division, is dedicated to determining the epigenetic, genetic, molecular and cellular origins of cancer, Parkinson's and other diseases and translating those findings into effective therapies. The Institute's scientists work in onsite laboratories and participate in collaborative partnerships that span the globe.

About The Rockefeller University

The Rockefeller University is the world's leading biomedical research university and is dedicated to conducting innovative, high-quality research to improve the understanding of life for the benefit of humanity. Our 79 laboratories conduct research in neuroscience, immunology, biochemistry, genomics, and many other areas, and a community of 1,800 faculty, students, postdocs, technicians, clinicians, and administrative personnel work on our 14-acre Manhattan campus. Our unique approach to science has led to some of the world's most revolutionary and transformative contributions to biology and medicine. During Rockefeller's 115-year history, 24 of our scientists have won Nobel Prizes, 21 have won Albert Lasker Medical Research Awards, and 20 have garnered the National Medal of Science, the highest science award given by the United States.

Van Andel Research Institute

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