Mutator phenotype of Caenorhabditis elegans DNA damage checkpoint mutants.
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.
Harris
Jasper
J
Department of Biology, University of North Carolina, NC 27599-3280, USA.
Lowden
Mia
M
Clejan
Iuval
I
Tzoneva
Monika
M
Thomas
James H
JH
Hodgkin
Jonathan
J
Ahmed
Shawn
S
D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D018816:Genes, cdc; D008969:Molecular Sequence Data; D010641:Phenotype; D017384:Sequence Deletion; D034501:Telomere-Binding Proteins / Q000235:genetics
D029742:Caenorhabditis elegans Proteins; C403443:MRT-2 protein, C elegans; D034501:Telomere-Binding Proteins; C438752:clk-2 protein, C elegans