Identification of conserved pathways of DNA-damage response and radiation protection by genome-wide RNAi.
Ionizing radiation is extremely harmful for human cells, and DNA double-strand breaks (DSBs) are considered to be the main cytotoxic lesions induced. Improper processing of DSBs contributes to tumorigenesis, and mutations in DSB response genes underlie several inherited disorders characterized by cancer predisposition. Here, we performed a comprehensive screen for genes that protect animal cells against ionizing radiation. A total of 45 C. elegans genes were identified in a genome-wide RNA interference screen for increased sensitivity to ionizing radiation in germ cells. These genes include orthologs of well-known human cancer predisposition genes as well as novel genes, including human disease genes not previously linked to defective DNA-damage responses. Knockdown of eleven genes also impaired radiation-induced cell-cycle arrest, and seven genes were essential for apoptosis upon exposure to irradiation. The gene set was further clustered on the basis of increased sensitivity to DNA-damaging cancer drugs cisplatin and camptothecin. Almost all genes are conserved across animal phylogeny, and their relevance for humans was directly demonstrated by showing that their knockdown in human cells results in radiation sensitivity, indicating that this set of genes is important for future cancer profiling and drug development.
van Haaften
Gijs
G
Hubrecht Laboratory, Center for Biomedical Genetics, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands.
Romeijn
Ron
R
Pothof
Joris
J
Koole
Wouter
W
Mullenders
Leon H F
LH
Pastink
Albert
A
Plasterk
Ronald H A
RH
Tijsterman
Marcel
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000502:physiology / Q000528:radiation effects; D029742:Caenorhabditis elegans Proteins / Q000145:classification / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D004249:DNA Damage; D017238:Genes, Helminth / Q000502:physiology*; D016678:Genome / Q000528:radiation effects; D005854:Germ Cells / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D034622:RNA Interference; D011836:Radiation Tolerance; D011839:Radiation, Ionizing
D029742:Caenorhabditis elegans Proteins