| 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
|
| Resource |
| DNA material |
pCMV-VSV-G-RSV-Rev (RDB04393)
pCAG-HIVgp (RDB04394)
pENTR4-H1tetOx1 (RDB07916)
CS-RfA-ETBsd (RDB07917) |
