title: Synthetic cytotoxicity: digenic interactions with TEL1/ATM mutations reveal sensitivity to low doses of camptothecin.
abstract: Many tumors contain mutations that confer defects in the DNA-damage response and genome stability. DNA-damaging agents are powerful therapeutic tools that can differentially kill cells with an impaired DNA-damage response. The response to DNA damage is complex and composed of a network of coordinated pathways, often with a degree of redundancy. Tumor-specific somatic mutations in DNA-damage response genes could be exploited by inhibiting the function of a second gene product to increase the sensitivity of tumor cells to a sublethal concentration of a DNA-damaging therapeutic agent, resulting in a class of conditional synthetic lethality we call synthetic cytotoxicity. We used the Saccharomyces cerevisiae nonessential gene-deletion collection to screen for synthetic cytotoxic interactions with camptothecin, a topoisomerase I inhibitor, and a null mutation in TEL1, the S. cerevisiae ortholog of the mammalian tumor-suppressor gene, ATM. We found and validated 14 synthetic cytotoxic interactions that define at least five epistasis groups. One class of synthetic cytotoxic interaction was due to telomere defects. We also found that at least one synthetic cytotoxic interaction was conserved in Caenorhabditis elegans. We have demonstrated that synthetic cytotoxicity could be a useful strategy for expanding the sensitivity of certain tumors to DNA-damaging therapeutics.
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Li
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: O'Neil
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Noushin
authors.initials: N
authors.lastname: Moshgabadi
authors.affiliation: Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada hieter@msl.ubc.ca.
authors.forename: Philip
authors.initials: P
authors.lastname: Hieter
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics; D002166:Camptothecin / Q000737:chemistry*; D004249:DNA Damage; D004843:Epistasis, Genetic; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D016615:Telomere / Q000235:genetics; D059004:Topoisomerase I Inhibitors / Q000737:chemistry
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D029701:Saccharomyces cerevisiae Proteins; D059004:Topoisomerase I Inhibitors; D017346:Protein Serine-Threonine Kinases; C513623:TEL1 protein, S cerevisiae; D002166:Camptothecin
keywords: DNA damage response; DNA-damaging agents; conditional synthetic lethality; genetic interaction; synthetic cytotoxicity