Wednesday, March 7, 2012

Study Reveals How Protein Machinery Binds and Wraps DNA to Start Replication - Karen McNulty Walsh & Peter Genzer -

UPTON, NY — 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.

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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.

“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.”

In a typical bacterial genome, comprised of several million base pairs — the “letters” of the genetic code — there is only one such origin. However, in more complex eukaryotic organisms, such as humans with a genome of 3.4 billion base pairs, there may be tens of thousands of replication origins so that DNA replication can be carried out simultaneously at these sites to duplicate the genome in a reasonable time.

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.

“This level of detail on the shape of the origin recognition complex and its interaction with DNA provides insight into a key cellular process, the initiation of DNA replication,” said Daniel Janes, who oversees DNA replication grants at the National Institutes of Health’s National Institute of General Medical Sciences, which partially supported the work. “Because DNA replication is closely tied to cell division, a thorough understanding of the process may lead to new ways to fight the uncontrolled cell division that characterizes cancer.”

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