Natural variation in a single amino acid substitution underlies physiological responses to topoisomerase II poisons.

ABSTRACT: Many chemotherapeutic drugs are differentially effective from one patient to the next. Understanding the causes of this variability is a critical step towards the development of personalized treatments and improvements to existing medications. Here, we investigate sensitivity to a group of anti-neoplastic drugs that target topoisomerase II using the model organism Caenorhabditis elegans. We show that wild strains of C. elegans vary in their sensitivity to these drugs, and we use an unbiased genetic approach to demonstrate that this natural variation is explained by a methionine-to-glutamine substitution in topoisomerase II (TOP-2). The presence of a non-polar methionine at this residue increases hydrophobic interactions between TOP-2 and its poison etoposide, as compared to a polar glutami

SUBMITTER: Zdraljevic S 

PROVIDER: S-EPMC5529024 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature