C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein.
BACKGROUND
In response to genotoxic stress, cells activate checkpoint pathways that lead to a transient cell cycle arrest that allows for DNA repair or to apoptosis, which triggers the demise of genetically damaged cells.


RESULTS
During positional cloning of the C. elegans rad-5 DNA damage checkpoint gene, we found, surprisingly, that rad-5(mn159) is allelic with clk-2(qm37), a mutant previously implicated in regulation of biological rhythms and life span. However, clk-2(qm37) is the only C. elegans clock mutant that is defective for the DNA damage checkpoint. We show that rad-5/clk-2 acts in a pathway that partially overlaps with the conserved C. elegans mrt-2/S. cerevisiae RAD17/S. pombe rad1(+) checkpoint pathway. In addition, rad-5/clk-2 also regulates the S phase replication checkpoint in C. elegans. Positional cloning reveals that the RAD-5/CLK-2 DNA damage checkpoint protein is homologous to S. cerevisiae Tel2p, an essential DNA binding protein that regulates telomere length in yeast. However, the partial loss-of-function C. elegans rad-5(mn159) and clk-2(qm37) checkpoint mutations have little effect on telomere length, and analysis of the partial loss-of-function of S. cerevisiae tel2-1 mutant failed to reveal typical DNA damage checkpoint defects.


CONCLUSIONS
Using C. elegans genetics we define the novel DNA damage checkpoint protein RAD-5/CLK-2, which may play a role in oncogenesis. Given that Tel2p has been shown to bind to a variety of nucleic acid structures in vitro, we speculate that the RAD-5/CLK-2 checkpoint protein may act at sites of DNA damage, either as a sensor of DNA damage or to aid in the repair of damaged DNA.
Ahmed
S
S
MRC Laboratory of Molecular Biology, CB2 2QH, Hills Road, Cambridge, United Kingdom.
Alpi
A
A
Hengartner
M O
MO
Gartner
A
A
D000251:Adenosine Triphosphatases; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D004265:DNA Helicases; D004843:Epistasis, Genetic; D019143:Evolution, Molecular; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D034501:Telomere-Binding Proteins
D029742:Caenorhabditis elegans Proteins; D005656:Fungal Proteins; D029701:Saccharomyces cerevisiae Proteins; D034501:Telomere-Binding Proteins; C438752:clk-2 protein, C elegans; D000251:Adenosine Triphosphatases; C076225:RAD5 protein, S cerevisiae; D004265:DNA Helicases