Synthetic lethal genetic interactions that decrease somatic cell proliferation in Caenorhabditis elegans identify the alternative RFC CTF18 as a candidate cancer drug target.
Somatic mutations causing chromosome instability (CIN) in tumors can be exploited for selective killing of cancer cells by knockdown of second-site genes causing synthetic lethality. We tested and statistically validated synthetic lethal (SL) interactions between mutations in six Saccharomyces cerevisiae CIN genes orthologous to genes mutated in colon tumors and five additional CIN genes. To identify which SL interactions are conserved in higher organisms and represent potential chemotherapeutic targets, we developed an assay system in Caenorhabditis elegans to test genetic interactions causing synthetic proliferation defects in somatic cells. We made use of postembryonic RNA interference and the vulval cell lineage of C. elegans as a readout for somatic cell proliferation defects. We identified SL interactions between members of the cohesin complex and CTF4, RAD27, and components of the alternative RFC(CTF18) complex. The genetic interactions tested are highly conserved between S. cerevisiae and C. elegans and suggest that the alternative RFC components DCC1, CTF8, and CTF18 are ideal therapeutic targets because of their mild phenotype when knocked down singly in C. elegans. Furthermore, the C. elegans assay system will contribute to our knowledge of genetic interactions in a multicellular animal and is a powerful approach to identify new cancer therapeutic targets.
Department of Medical Genetics, The University of British Columbia, Vancouver, BC, Canada.
Jessica
J
McLellan
Nigel
N
O'Neil
Sanja
S
Tarailo
Jan
J
Stoepel
Jennifer
J
Bryan
Ann
A
Rose
Philip
P
Hieter
D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D019070:Cell Lineage; D049109:Cell Proliferation; D043171:Chromosomal Instability / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D052138:Genes, Neoplasm / Q000235:genetics; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics; D000097722:Cohesins
D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D046912:Multiprotein Complexes; D000097722:Cohesins