Magic™ Anti-BRCA1 monoclonal antibody

Aflatoxin B1 (AFB(1)) is a mycotoxin widely distributed in a variety of food commodities and exhibits strong toxicity toward multiple tissues and organs. However, little is known about its neurotoxicity and the associated mechanism. In this study, we observed that brain integrity was markedly damaged in mice after intragastric administration of AFB(1)(300 mu g/kg/day for 30 days). The toxicity of AFB(1)on neuronal cells and the underlying mechanisms were then investigated in the neuroblastoma cell line IMR-32. A cell viability assay showed that the IC50 values of AFB(1)on IMR-32 cells were 6.18 mu g/mL and 5.87 mu g/mL after treatment for 24 h and 48 h, respectively. ROS levels in IMR-32 cells increased significantly in a time- and AFB(1)concentration-dependent manner, which was associated with the upregulation ofNOX2, and downregulation ofOXR1,SOD1, andSOD2. Substantial DNA damage associated with the downregulation ofPARP1,BRCA2, andRAD51was also observed. Furthermore, AFB(1)significantly induced S-phase arrest, which is associated with the upregulation ofCDKN1A,CDKN2C, andCDKN2D. Finally, AFB(1)induced apoptosis involvingCASP3andBAX. Taken together, AFB(1)manifests a wide range of cytotoxicity on neuronal cells including ROS accumulation, DNA damage, S-phase arrest, and apoptosis-all of which are key factors for understanding the neurotoxicology of AFB(1).

The APEX2 gene encodes APE2, a nuclease related to APE1, the apurinic/apyrimidinic endonuclease acting in base excision repair. Loss of APE2 is lethal in cells with mutated BRCA1 or BRCA2, making APE2 a prime target for homologous recombination-defective cancers. However, because the function of APE2 in DNA repair is poorly understood, it is unclear why BRCA-deficient cells require APE2 for viability. Here we present the genetic interaction profiles of APE2, APE1, and TDP1 deficiency coupled to biochemical and structural dissection of APE2. We conclude that the main role of APE2 is to reverse blocked 30 DNA ends, problematic lesions that preclude DNA synthesis. Our work also suggests that TOP1 processing of genomic ribonucleotides is the main source of 30 -blocking lesions relevant to APEX2-BRCA1/2 synthetic lethality. The exquisite sensitivity of BRCA-deficient cells to 30 blocks indicates that they represent a tractable vulnerability in homologous recombination-deficient tumor cells.