Hofmann, E. R., Milstein, S., Boulton, S. J., Ye, M. J., Hofmann, J. J., Stergiou, L., Gartner, A., Vidal, M., Hengartner, M. O. (November 2002) Caenorhabditis elegans HUS-1 is a DNA damage checkpoint protein required for genome stability and EGL-1-mediated apoptosis. Current Biology, 12 (22). pp. 1908-1918. ISSN 0960-9822
Abstract
BACKGROUND:The inability to efficiently repair DNA damage or remove cells with severely damaged genomes has been linked to several human cancers. Studies in yeasts and mammals have identified several genes that are required for proper activation of cell cycle checkpoints following various types of DNA damage. However, in metazoans, DNA damage can induce apoptosis as well. How DNA damage activates the apoptotic machinery is not fully understood. RESULTS:We demonstrate here that the Caenorhabditis elegans gene hus-1 is required for DNA damage-induced cell cycle arrest and apoptosis. Following DNA damage, HUS-1 relocalizes and forms distinct foci that overlap with chromatin. Relocalization does not require the novel checkpoint protein RAD-5; rather, relocalization appears more frequently in rad-5 mutants, suggesting that RAD-5 plays a role in repair. HUS-1 is required for genome stability, as demonstrated by increased frequency of spontaneous mutations, chromosome nondisjunction, and telomere shortening. Finally, we show that DNA damage increases expression of the proapoptotic gene egl-1, a response that requires hus-1 and the p53 homolog cep-1. CONCLUSIONS:Our findings suggest that the RAD-5 checkpoint protein is not required for HUS-1 to relocalize following DNA damage. Furthermore, our studies reveal a new function of HUS-1 in the prevention of telomere shortening and mortalization of germ cells. DNA damage-induced germ cell death is abrogated in hus-1 mutants, in part, due to the inability of these mutants to activate egl-1 transcription in a cep-1/p53-dependent manner. Thus, HUS-1 is required for p53-dependent activation of a BH3 domain protein in C. elegans.
| Item Type: | Paper |
|---|---|
| Subjects: | organism description > animal > C elegans bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis |
| CSHL Authors: | |
| Communities: | CSHL labs > Hengartner lab |
| Depositing User: | Matt Covey |
| Date: | November 2002 |
| Date Deposited: | 08 Jan 2014 20:17 |
| Last Modified: | 08 Jan 2014 20:17 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/28720 |
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