From Brookhaven Lab: “Study Reveals How Protein Machinery Binds and Wraps DNA to Start Replication”

Molecular-level details of mechanism may point to ways to block unwanted cell division

March 6, 2012
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“Before any cell — healthy or cancerous — can divide, it has to replicate its DNA. So scientists who want to know how normal cells work — and perhaps how to stop abnormal ones — are keen to understand this process. As a step toward that goal, scientists at the U.S. Department of Energy’s Brookhaven National Laboratory and collaborators have deciphered molecular-level details of the complex choreography by which intricate cellular proteins recognize and bind to DNA to start the replication process. The study is published in the March 7, 2012, issue of the journal Structure.

‘Every cell starts to replicate its genome at defined DNA sites called ‘origins of replication,’ said Huilin Li, a biologist at Brookhaven Lab and Stony Brook University, who led the study. ‘A cell finds those origins in its vast genome with a protein machine called the origin recognition complex, or ORC.

The goal of the current effort was to understand the first steps of the enormously complex task of duplicating a eukaryotic genome: how the protein machinery ORC recognizes and binds to the origin DNA, and how the origin-bound ORC enables the attachment of additional protein machinery that unwinds the DNA double helix into two single strands in preparation for DNA copying.

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The DNA replication origin recognition complex (ORC) is a six-protein machine with a slightly twisted half-ring structure (yellow). ORC is proposed to wrap around and bend approximately 70 base pairs of double stranded DNA (red and blue). When a replication initiator Cdc6 (green) joins ORC, the partial ring is now complete and ready to load another protein onto the DNA. This last protein (not shown) is the enzyme that unwinds the double stranded DNA so each strand can be replicated. No image credit.

Jingchuan (Jim) Sun, a Brookhaven biologist who works with Li, used an imaging method known as cryo-electron microscopy to make higher resolution images of the eukaryotic ORC, in isolation, as it binds to DNA, and one step further in the process, when another protein unit binds to activate the entire structure. The research team used proteins from baker’s yeast, which is a model system for eukaryotes.”

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Jingchuan (Jim) Sun and Huilin Li. No photo credit

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One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE’s Office of Science by Brookhaven Science Associates, a limited-liability company founded by Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.
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