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C. elegans as a platform to characterize genes and therapeutics affecting genome stability Ye, Bin


Genome stability is essential for survival in all living organisms. Perturbations of genome stability can lead to cancer and other diseases in human. Dysfunction of genome care-taking genes and exposure to external genotoxins are the two major drivers of genomic instability. Here, we used a model organism, C. elegans to study these factors and how they interact to affect genome stability. We first generated a chemi-genetic interaction map as a preliminary reference for characterizing genes and agents. From there, we elucidated the mechanisms of action for an emerging anticancer therapeutic CX-5461. CX-5461 turned out to be a multi-modal agent that exhibits genotypic sensitivity, mutagenicity and photosensitivity. Next, we identified a few genetic interactions within and between double-strand break repair pathways in C. elegans, which have implications in the response to both endogenous and exogenous DNA damage. We also characterized a less-understood gene SMRC-1, an annealing helicase. Loss of SMRC-1 results in copy number variations, and SMRC-1 is synthetic lethal with a number of DNA damage response genes. Our work concludes that C. elegans is a great platform to untangle the sophisticated complexity in genome maintenance, and provide meaningful insights for prospective anticancer therapeutic development.

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