2002 European Worm Meeting abstract 20
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| 1 | Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA |
| 2 | Institute for Molecular Biology, Winterthurerstrasse 190, CH 8057 Zürich, Switzerland |
| 3 | Graduate Program in Genetics, Department of Molecular Genetics and Microbiology, SUNY at Stony Brook, Stony Brook, New York 11794, USA |
| 4 | Dana-Farber Cancer Institute, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA |
| 5 | Max-Planck-Institute for Biochemistry, Department of Cell Biology, Am Klopferspitz 18a, Martinsried 82152, Germany |
Tumorigenesis is characterized by the accumulation of genetic mutations, rearrangements, amplifications, and deletions, all of which drive the progressive transformation of normal cells into highly malignant derivatives. Therefore it is essential for cells to have precise and efficient means to maintain the integrity of the genome. Damage to DNA triggers checkpoint controls that result in cell cycle arrest and repair of the lesion. In metazoans, a second option is the programmed demise of the cell, possibly due to extensive damage that is not rectifiable. Loss of communication between the DNA lesion and the apoptotic program, which allows the persistence of cells with damaged and/or unstable genomes, can lead to tumorigenesis.
In C. elegans, gamma irradiation induces apoptotic cell death of meiotic germ cells as well as proliferation arrest of mitotic germ cells. DNA damage-mediated apoptosis is dependent on ced-3, ced-4 and is negatively regulated by ced-9. The positive death regulator, egl-1, participates in, but is not essential for radiation-induced apoptosis.
Recently, three mutants - op241, rad-5(mn159), and mrt-2(e2663) - have been identified in C. elegans that block DNA damage induced apoptosis and cell cycle arrest1-3.
We have recently mapped op241 to the left arm of LGI between unc-11 and stu-4. Sequence analysis revealed a mutation in the homologue for the S. pombe hus1+ checkpoint gene. In addition, we have isolated a deletion mutant of hus-1(op244) from a deletion library. Characterization of op244 reveals other phenotypes suggesting a role for hus-1 in maintaining genome stability and telomere maintenance. HUS-1 is a nuclear protein that is expressed in the germline. Nuclear localization of HUS-1 is dependent on the checkpoint genes mrt-2 and hpr-9, but not rad-5. Following DNA damage, HUS-1 re-localizes to putative sites of DNA damage. Re-localization of HUS-1 is enhanced in rad-5 (nm159) and rad-51(RNAi) backgrounds, suggesting a role for these proteins in DNA repair. Finally, egl-1 is upregulated following DNA damage in a HUS-1 dependent manner.
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3. Ahmed, S., Alpi, A., Hengartner, M. O. & Gartner, A. Curr Biol 11, 1934-44. (2001).