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Curr Biol. 2001 Dec 11;11(24):1934-44.

C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein.

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1
MRC Laboratory of Molecular Biology, CB2 2QH, Hills Road, Cambridge, United Kingdom.

Abstract

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.

PMID:
11747819
DOI:
10.1016/s0960-9822(01)00604-2
[Indexed for MEDLINE]
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