Gene interactions in the DNA damage-response pathway identified by genome-wide RNA-interference analysis of synthetic lethality

Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):12992-6. doi: 10.1073/pnas.0403131101. Epub 2004 Aug 23.


Here, we describe a systematic search for synthetic gene interactions in a multicellular organism, the nematode Caenorhabditis elegans. We established a high-throughput method to determine synthetic gene interactions by genome-wide RNA interference and identified genes that are required to protect the germ line against DNA double-strand breaks. Besides known DNA-repair proteins such as the C. elegans orthologs of TopBP1, RPA2, and RAD51, eight genes previously unassociated with a double-strand-break response were identified. Knockdown of these genes increased sensitivity to ionizing radiation and camptothecin and resulted in increased chromosomal nondisjunction. All genes have human orthologs that may play a role in human carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / physiology
  • DNA Damage / genetics
  • DNA Damage / physiology
  • DNA Repair / genetics*
  • DNA Repair / physiology
  • RNA Interference / physiology*