Sci. Aging Knowl. Environ., 3 April 2002
A Jump-Start for Replication: When DNA-copying machinery conks out, Bloom syndrome helicase brings repair proteins to the rescue (DNA damage)
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/13/nw45
Key Words: BLM RAD50 MRE11 NBS1 replication fork
Abstract: Just as unwinding on a beach is good for your mental well-being, unwinding your DNA is good for your cells. A protein that untwists DNA helps cells bring repair molecules to sites where damage can occur as DNA is copied, scientists have now shown. The results reveal one possible way that insufficient amounts of the protein can result in the genetic chaos that underlies a rare but devastating affliction.
DNA helicase enzymes wrench apart double-stranded DNA, a crucial step in repairing and copying DNA. When certain helicases are missing, debilitating diseases result. For instance, people whose cells don't make the BLM helicase suffer from Bloom syndrome, an inherited illness characterized by a high risk of cancer. Individuals who lack a related protein--the WRN helicase--exhibit signs of rapid aging (see "Of Hyperaging and Methuselah Genes"), and, like those with Bloom syndrome, they are unusually likely to get cancer. Scientists are eager to understand how a dearth of these proteins triggers such symptoms. A decade of work suggests that BLM keeps a cell's genome fit: Cells without BLM contain chromosomes that are broken or have large chunks swapped into new positions. Studies in the last 2 years suggested that BLM binds to proteins known to flag and repair DNA damage, including a cluster of proteins called RMN. But how BLM affects the function of this repair machinery has been unclear.
Franchitto and Pichierri investigated whether a lack of BLM hinders RMN's ability to home in on damage. The researchers obtained cells from patients with Bloom syndrome and treated them with hydroxyurea, which halts DNA-copying machinery. Then they added glowing antibodies that bind to the RMN complex and illuminate its cellular location. In control cells that contain BLM, RMN flocks to particular sites in the nucleus and appears as a constellation of radiant dots; previous studies suggested that those sites are where DNA-copying machinery stalls. But in cells without funtional BLM, RMN remains dispersed throughout the nucleus and no dots appear. By recruiting RMN, the researchers propose, BLM helps protect sites where DNA-copying machinery has frozen. In the absence of BLM, DNA is more likely to break at those sites. The process of repairing such fractures can splice chunks of DNA into new locations, which could explain the profound rearrangement of chromosomes observed in Bloom syndrome patients.
The idea that BLM prevents DNA-copying problems from turning into bigger messes "makes a lot of sense," says cell biologist Robert Abraham of the Burnham Institute in La Jolla, California, although he cautions that the details of how BLM might encourage RMN to target trouble spots are still fuzzy. But the results hint that, by recruiting RMN to paralyzed replication machinery, BLM might prevent cells from doing the genome shuffle.
--R. John Davenport; suggested by Patrick Kaminker
A. Franchitto and P. Pichierri, Bloom's syndrome protein is required for correct relocalization of RAD50/MRE11/NBS1 complex after replication fork arrest. J. Cell Bio., 26 March 2002 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: R. J. Davenport, A Jump-Start for Replication: When DNA-copying machinery conks out, Bloom syndrome helicase brings repair proteins to the rescue (DNA damage). Science's SAGE KE (3 April 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/13/nw45
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