Gene interactions in the DNA damage-response pathway identified by genome-wide RNA-interference analysis of synthetic lethality
- Gijs van Haaften,
- Nadine L. Vastenhouw,
- Ellen A. A. Nollen,
- Ronald H. A. Plasterk*, and
- Marcel Tijsterman*
- Hubrecht Laboratory, Center for Biomedical Genetics, Uppsalalaan 8, 3584 CT, Utrecht, The Netherlands
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Edited by Robert H. Horvitz, Massachusetts Institute of Technology, Cambridge, MA, and approved July 19, 2004 (received for review May 4, 2004)
Abstract
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.
Footnotes
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↵ * To whom correspondence may be addressed. E-mail: plasterk{at}niob.knaw.nl and tijsterman{at}niob.knaw.nl.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: DSB, double-strand break; RNAi, RNA interference.
- Copyright © 2004, The National Academy of Sciences
