Description
Mirin is an inhibitor of the Mre11/Rad50/Nbs1 (MRN) complex, which functions as a DNA damage sensor and activates the DNA repair enzyme ataxia-telangiectasia mutated kinase (ATM). It inhibits phosphorylation of H2AX induced by DNA containing dsDNA breaks (DSBs), indicating decreased ATM activation, with an IC
50 value of 66 μM in
X. laevis cell-free extracts. Mirin (100 μM) also inhibits the exonuclease activity of Mre11 in a cell-free assay. It induces cell cycle arrest at the G
2 phase in TOSA4 cells and inhibits homology-dependent repair in HEK293 cells in a concentration-dependent manner. Nanoparticle-encapsulated mirin (50 mg/kg) reduces tumor growth in an LA-N-5 mouse xenograft model.
Uses
The Mre11-Rad50-Nbs1 (MRN) complex acts as a DNA damage sensor, maintains genome stability during DNA replication, and activates and recruits ataxia-telangiectasia mutated (ATM) to damaged DNA. The genes that encode the MRN proteins are all essential for cell viability, so functional studies of MRN cannot involve deletion of these genes. Mirin is an inhibitor of MRN, inhibiting MRN-dependent phosphorylation of histone H2AX (IC50 = 66 μM). Through its effects on MRN, mirin prevents activation of ATM. Inhibition of MRN centers on the ability of mirin to block the nuclease activity of Mre11, rather than altering DNA-binding or MRN complex formation. In cells, mirin induces G2 arrest, abolishes the radiation-induced G2/M checkpoint, and prevents homology-directed repair of DNA damage.[Cayman Chemical]
Uses
Mirin has been used:
- as a small molecule inhibitor of meiotic recombination 11 (MRE11), in the pre-treatment of HCT116 wildtype cells before irradiation
- as Mre11 inhibitior in BSC-1 cells infected with simian virus 40
- in the pre-treatment of W12E cells for quantification of human papilloma virus (HPV) episome levels and to potentiate the effect of polyamide-25 (PA-25)
Biochem/physiol Actions
Mirin is an inhibitor of the Mre11-Rad50-Nbs1 complex. It disrupts nuclease activity of Mre11 and thus, the ability to repair DNA double strand breaks.
References
[1] AUDE DUPRÉ. A forward chemical genetic screen reveals an inhibitor of the Mre11–Rad50–Nbs1 complex[J]. Nature chemical biology, 2008, 4 2: 119-125. DOI:
10.1038/nchembio.63
