Genome stability in Caenorhabditis elegans

Abstract

Genome stability is closely linked to cancer. Most, if not all tumor cells show some form of genome instability, mutations can range from single point mutations to gross chromosomal rearrangements and aneuploidy. Genome instability is believed to be the driving force behind tumorigenesis. In order to discover genes that keep an organism's genome stable, we made use of the powerful genetics of the model organism C. elegans. In the nematode C. elegans, genes can systematically be silenced using RNA interference (RNAi). we setup several assays to monitor genome stability in C. elegans and developed a method to do high-throughput genome-wide screens. Several types of cancer show micro satellite instability, using genome-wide RNAi, we screened for genes that protect the genome against frame shift mutations, and indeed found othologs of known human cancer genes as well as novel genes. Next we screened for genes that protect against DNA double strand breaks, since improper processing of DNA breaks can result in gross chromosomal rearrangements. The method described in the paper allows the identification of synthetic lethal interactions in C. elegans using the combination of RNAi and a genetic mutant. Recently we did a screen for genes required for resistance against ionizing radiation. In this screen we found several orthologs of genes known to predispose to cancer, as well as genes not previously linked to cancer. We knocked down orthologous genes in a human cell line and indeed the human cells became radiation sensitive, proving functional conservation of the genes. The presence of known genome stability genes validates the experimental setup; novel genes are likely to play a role in tumor biology.