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About the Authors:
Stefan Zdraljevic
Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing - original draft, Writing - review & editing
Affiliations Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, Illinois, United States of America, Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America
ORCID http://orcid.org/0000-0003-2883-4616
Christine Strand
Roles Conceptualization, Investigation, Methodology, Writing - original draft
Affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
ORCID http://orcid.org/0000-0001-5783-6667
Hannah S. Seidel
Roles Resources, Writing - original draft
Affiliation: Biology Department, Eastern Michigan University, Ypsilanti, Michigan, United States of America
ORCID http://orcid.org/0000-0002-4831-8646
Daniel E. Cook
Roles Data curation, Resources, Software
Affiliations Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, Illinois, United States of America, Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America
John G. Doench
Roles Conceptualization, Data curation, Formal analysis, Investigation, Writing - original draft, Writing - review & editing
Affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
ORCID http://orcid.org/0000-0002-3707-9889
Erik C. Andersen
Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
* E-mail: [email protected]
Affiliations Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, Illinois, United States of America, Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, United States of America, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, United States of America
ORCID http://orcid.org/0000-0003-0229-9651Abstract
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 glutamine. We hypothesize that this stabilizing interaction results in increased genomic instability in strains that contain a methionine residue....