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.