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Originally published as Genetics Published Articles Ahead of Print on September 1, 2006.

Genetics, Vol. 174, 601-616, October 2006, Copyright © 2006
doi:10.1534/genetics.106.058701

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Mutator Phenotype of Caenorhabditis elegans DNA Damage Checkpoint Mutants

Jasper Harris*,1, Mia Lowden*,{dagger}, Iuval Clejan{dagger},{ddagger}, Monika Tzoneva§, James H. Thomas§, Jonathan Hodgkin** and Shawn Ahmed*,{dagger},{ddagger},{dagger}{dagger},2

* Department of Biology, {dagger} Department of Genetics, {ddagger} Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-3280, § Department of Genome Sciences, University of Washington, Seattle, Washington 98195, ** Genetics Unit, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom and {dagger}{dagger} MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom

2 Corresponding author: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-3280.
E-mail: shawn{at}med.unc.edu

DNA damage response proteins identify sites of DNA damage and signal to downstream effectors that orchestrate either apoptosis or arrest of the cell cycle and DNA repair. The C. elegans DNA damage response mutants mrt-2, hus-1, and clk-2(mn159) displayed 8- to 15-fold increases in the frequency of spontaneous mutation in their germlines. Many of these mutations were small- to medium-sized deletions, some of which had unusual sequences at their breakpoints such as purine-rich tracts or direct or inverted repeats. Although DNA-damage-induced apoptosis is abrogated in the mrt-2, hus-1, and clk-2 mutant backgrounds, lack of the apoptotic branch of the DNA damage response pathway in cep-1/p53, ced-3, and ced-4 mutants did not result in a Mutator phenotype. Thus, DNA damage checkpoint proteins suppress the frequency of mutation by ensuring that spontaneous DNA damage is accurately repaired in C. elegans germ cells. Although DNA damage response defects that predispose humans to cancer are known to result in large-scale chromosome aberrations, our results suggest that small- to medium-sized deletions may also play roles in the development of cancer.


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