Gross Chromosomal Rearrangements and Elevated Recombination at an Inducible Site-Specific Replication Fork Barrier

Genomic rearrangements linked to aberrant recombination are associated with cancer and human genetic diseases. Such recombination has indirectly been linked to replication fork stalling. Using fission yeast, we have developed a genetic system to block replication forks at nonhistone/DNA complexes lo...

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Bibliographic Details
Published in:Cell 2005-06, Vol.121 (5), p.689-702
Main Authors: Lambert, Sarah, Watson, Adam, Sheedy, Daniel M., Martin, Ben, Carr, Antony M.
Format: Article
Language:English
Subjects:
Chromosomes - physiology
DNA Replication - physiology
DNA-Binding Proteins - metabolism
Fluorescent Antibody Technique, Indirect
Recombination, Genetic - physiology
Schizosaccharomyces - genetics
Schizosaccharomyces - physiology
Schizosaccharomyces pombe Proteins - metabolism
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Summary:Genomic rearrangements linked to aberrant recombination are associated with cancer and human genetic diseases. Such recombination has indirectly been linked to replication fork stalling. Using fission yeast, we have developed a genetic system to block replication forks at nonhistone/DNA complexes located at a specific euchromatic site. We demonstrate that stalled replication forks lead to elevated intrachromosomal and ectopic recombination promoting site-specific gross chromosomal rearrangements. We show that recombination is required to promote cell viability when forks are stalled, that recombination proteins associate with sites of fork stalling, and that recombination participates in deleterious site-specific chromosomal rearrangements. Thus, recombination is a “double-edged sword,” preventing cell death when the replisome disassembles at the expense of genetic stability.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2005.03.022