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MBC in Press, published online ahead of print November 5, 2008
Mol. Biol. Cell 10.1091/mbc.E08-06-0565

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Submitted on June 5, 2008
Revised on October 20, 2008
Accepted on October 29, 2008

Recql5 Plays an Important Role in DNA Replication and Cell Survival Following Camptothecin Treatment

Yiduo Hu,* Xincheng Lu, Guangjin Zhou, Ellen L. Barnes, and Guangbin Luo

Department of Genetics, Case Comprehensive Cancer Center and University Hospitals, Case Western Reserve University, Cleveland, OH 44106

Monitoring Editor: Mark J. Solomon

Disruption of replication can lead to loss of genome integrity and increase of cancer susceptibility in mammals. Thus, a replication impediment constitutes a formidable challenge to these organisms. Recent studies indicate that homologous recombination (HR) plays an important role in suppressing genome instability and promoting cell survival following exposure to various replication inhibitors, including a topoisomerase I inhibitor, camptothecin (CPT). Here, we report that the deletion of RecQ helicase Recql5 in mouse ES cells and embryonic fibroblast (MEF) cells resulted in a significant increase in CPT sensitivity and a profound reduction in DNA replication following the treatment with CPT, but not other DNA damaging agents. This CPT-induced cell death is replication dependent and occurs primarily after the cells had exited the first cell cycle after CPT treatment. Furthermore, we show that Recql5 functions nonredundantly with Rad51, a key factor for HR to protect mouse ES cells from CPT-induced cytotoxicity. These new findings strongly suggest that Recql5 plays an important role in maintaining active DNA replication to prevent the collapse of replication forks and the accumulation of DSBs in order to preserve genome integrity and to prevent cell death following replication stress as a result of topoisomerase I poisoning.

*Present address: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115.

Address correspondence to: Guangbin Luo (guangbin.luo{at}case.edu)






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