RRC ID 56567
Author Hirokawa T, Shiotani B, Shimada M, Murata K, Johmura Y, Haruta M, Tahara H, Takeyama H, Nakanishi M.
Title CBP-93872 inhibits NBS1-mediated ATR activation, abrogating maintenance of the DNA double-strand break-specific G2 checkpoint.
Journal Cancer Res
Abstract CBP-93872 was previously identified as a G2 checkpoint inhibitor using a cell-based high-throughput screening system. However, its molecular actions as well as cellular targets are largely unknown. Here, we uncovered the molecular mechanisms underlying abrogation of the G2 checkpoint by CBP-93872. CBP-93872 specifically abrogates the DNA double-stranded break (DSB)-induced G2 checkpoint through inhibiting maintenance but not initiation of G2 arrest because of specific inhibition of DSB-dependent ATR activation. Hence, ATR-dependent phosphorylation of Nbs1 and replication protein A 2 upon DSB was strongly suppressed in the presence of CBP-93872. CBP-93872 did not seem to inhibit DNA-end resection, but did inhibit Nbs1-dependent and ssDNA-induced ATR activation in vitro in a dose-dependent manner. Taken together, our results suggest that CBP-93872 is an inhibitor of maintenance of the DSB-specific G2 checkpoint and thus might be a strong candidate as the basis for a drug that specifically sensitizes p53-mutated cancer cells to DSB-inducing DNA damage therapy.
Volume 74(14)
Pages 3880-9
Published 2014-7-15
DOI 10.1158/0008-5472.CAN-13-3604
PII 0008-5472.CAN-13-3604
PMID 24876101
MeSH Aniline Compounds / pharmacology* Ataxia Telangiectasia Mutated Proteins / metabolism Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism* Cell Line, Tumor DNA Breaks, Double-Stranded / drug effects* Enzyme Activation / drug effects G2 Phase Cell Cycle Checkpoints / drug effects* Humans Mutation Nuclear Proteins / genetics Nuclear Proteins / metabolism* Phosphorylation Propanolamines / pharmacology* Protein Binding
IF 8.378
Times Cited 9
DNA material pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394) pENTR4-H1tetOx1 (RDB07916) CS-RfA-ETBsd (RDB07917)