We are surrounded by factors the can cause mutations or damage to our DNA,
creating instability in our genes which is detrimental to our survival. Our
cells however, work to maintain this natural stability by using a sophisticated
process called the DNA damage response (Gartner, A. et al). As every cell is
going through its cell cycle, this process monitors the genome for any damage
to the DNA due to genotoxic agents such as radiation or mutagenic organic
compounds. DNA damage response is carried out by the use of checkpoint proteins
which recognize damaged DNA at different stages of the cell cycle and trigger
one of two possible outcomes. (Ahmed, S. 2000)
RELEVANCE OF C. ELEGANS TO STUDYING HUMAN DAMAGE RESPONSE SYSTEMS
The level of similarity between the C. elegans genome and the human genome
makes it easy to understand why the nematode is a great model for studying
the DNA damage response system and the genes responsible for it (DDR genes).
In one study, Simon et al. carried out an experiment to find the genomic maps
of the DNA damage response in C. elegans. In this study, the researchers analyzed
the protein binding capabilities of the DDR genes. They were not only able to
identify 12 worm DDR orthologs, but also were able to find as many as 17 novel
genes in this species. Experiments were performed to see the phenotypic effect of
the absence of each of these genes, which allowed the researchers to better understand
the function of the genes identified. Damage to certain genes that gave rise to checkpoint
proteins resulted in abnormal phenotypes that increase the organism's susceptibility to
development of cancer.
EXAMPLES OF GENES STUDIED IN THIS FIELD
In a detailed study of checkpoint proteins Ahmed et al.,
while performing cloning experiments using PCR technology identified two
checkpoint alleles, rad-5 and clk-2 (Ahmed et. al. 2001). These two genes
among many others were found to comprise a great part of the organism's DNA
damage response system (Gartner, A, et al 2000), the existence of these proteins
was presented and certain characteristics were derived. The most important finding
of this study is that the checkpoint pathway is evolutionarily conserved. In other
words, a pathway was not generated de novo in the worm. It has been present for many
years and is probably present in similar forms in many other organisms, including humans.
The great amount of homology between C. elegans and humans makes this hypothesis much
more probable (Chalfie, M., 1998)
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RELEVANCE TO CANCER
We know that cancer arises from mutations and damage to DNA molecules
due to factors such as radiation. These factors cause alterations in our
DNA damage response system by disabling the checkpoint proteins, altering
the cell cycle arrest or changing the apoptotic pathway. The use of C. elegans
as a model for studying these pathways has provided us with an opportunity to
learn about human diseases as well. Button et. Al., using protein-protein mapping
identified a C. elegans checkpoint protein, CO4F12.3, which is an ortholog of a
human gene called hBCL3 (Boulton et. al. 2002). This human gene is often associated
with chromosomal translocation and proliferation in cancer cells. It is usually found
with damage in a type of human cancer called Chronic Lymphocytic Leukemia, a cancer
of blood cells. This introduces the possibility that hBLC3 is also involved in a
checkpoint pathway in human cells which would explain its translocation and amplification
in Chronic Leukemias.
references
1. Ahmed, S., Alpi, A., Hengartner, M. O., Gartner, A., 2001. C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint. Curr. Biol. 11(24), 1934-44
2. Boulton, S. J., Gartner, A., Reboul, J., Valgio, P., Dyson, N., Hill, D., Vidal, M., 2002. Combined Functional Genomic Maps of the C. elegans DNA Damage response. Science, 295, 127-131
3. Gartner,A., Milstein, S., Ahmed, S., Hodgkin, J., Hengartner, M.O., 2000. A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans. Mol. Cell. 5:435-443
4. Kuwabara, P. E., O'Neil, N.,2001. The use of functional genomics in C. elegans for studying human development and disease.J. Inherit. Metab. Dis. 24, 127-138