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Papers In Press, published online ahead of print August 10, 2006
Laboratory of Molecular Pharmacology, NCI, NIH, Bethesda, MD 20892
Corresponding Author: pommier{at}nih.gov
The Mre11-Rad50-Nbs1 (MRN) complex binds DNA double-strand breaks to repair DNA and activate checkpoints. We report MRN deficiency in 3 of the 7 colon carcinoma cell lines of the NCI Anticancer Drug Screen. To study MRN’s involvement in replication-mediated DNA double-strand breaks, we examined checkpoint responses to camptothecin, which induces replication-mediated DNA double-strand breaks after replication forks collide with topoisomerase I cleavage complexes. MRN-deficient cells were deficient for Chk2 activation, whereas Chk1 activation was independent of MRN. Chk2 activation was ATM-dependent, and associated with phosphorylation of Mre11 and Nbs1. Mre11 complementation in MRN-deficient HCT116 cells restored Chk2 activation as well as Rad50 and Nbs1 levels. Conversely, Mre11 downregulation by siRNA in HT29 cells inhibited Chk2 activation and downregulated Nbs1 and Rad50. Proteasome inhibition also restored Rad50 and Nbs1 levels in HCT116 cells suggesting that Mre11 stabilizes Rad50 and Nbs1. Chk2 activation was also defective in 3 out of the 4 MRN-proficient colorectal cell lines because of low Chk2 levels. Thus, 6 out of the 7 colon carcinoma cell lines from the NCI Anticancer Drug Screen are functionally Chk2-deficient in response to replication-mediated DNA double-strand breaks. We propose that Mre11 stabilizes Nbs1 and Rad50 and that MRN activates Chk2 downstream from ATM in response to replication-mediated DNA double-strand breaks. Chk2 deficiency in HCT116 is associated with defective S-phase checkpoint, prolonged G2 arrest and hypersensitivity to camptothecin. The high frequency of MRN and Chk2 deficiencies may contribute to genomic instability and therapeutic response to camptothecins in colorectal cancers.
J. Biol. Chem, 10.1074/jbc.M603747200
Submitted on April 19, 2006
Revised on August 10, 2006
Accepted on August 10, 2006
Defective MRE11-dependent activation of CHK2 by ATM in colorectal carcinoma cells in response toreplication-dependent DNA double-strand breaks
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