Genomic instability may play a role in causing organisms to age. Previous studies have indicated the amount of DNA repair performed is positively correlated with life span of the organism. Through heritable progeroid syndromes such as Bloom and Werner, characterized by a high incidence of genomic instability caused by mutations in RecQ helicases, it is possible to study the impact of genomic instability on the rate of aging of an organism. C. elegans have four RecQ helicases; two of these RecQ helicases share homology with the Bloom (
him-6) and Werner (
wrn-1) in humans. The C. elegans helicases KO2F3.1 and E03A3.3 are homologous to the human RecQL and RecQL5 respectively. Through studying the deletion mutants of
him-6 and
wrn-1, it may be possible to determine the role genomic instability plays in the aging process. It also becomes possible to study the roles of HIM-6, WRN-1, and other RecQ helicase in maintaining genomic stability. In order to understand the roles of the RecQ helicases in C. elegans, double mutants of different RecQ helicases will be created and then tested for a shortened lifespan and lowered brood size. Also, given the high incidence of genomic instability demonstrated by the loss of function of human homologs of RecQ helicases, the strains will be tested to determine if loss of function of one or multiple RecQ helicases results in a mutator phenotype. It is feasible that mutations in RecQ helicases may result in a mutator phenotype due to the fact that E03A3 has been identified in a screen to identify genes protecting the C. elegans genome (1). Preliminary results indicate that loss of function of
him-6 may cause a mutator phenotype due to the appearance of phenotypes previously unidentified in the original characterization of
him-6. To further identify pathways that
him-6 may play a role in, a systematic screen using an RNAi library of the first chromosome is being performed to identify suppressors of the
him-6 phenotype. 1) Pothof J., Van Haaften G., Thijssen K., Kamath RS., Fraser AG., Ahringer J., Plasterk RH., Tijsterman M.. Identification of genes that protect the C. elegans genome against mutations by genome-wide RNAi. Genes Dev. 2003 Feb 15;17(4):443-8