Genomic instability is a commonly observed toxicological effect in drug screening and results from DNA damage in the form of single and double strand breaks. DNA can be damaged by formation of DNA adducts, reactive oxygen species and DNA replication blockade. Accumulation of DNA damage leads to overall genomic instability and activation of cell cycle check point signaling. DNA damage in cells triggers phosphorylation of several targets involved in DNA repair and cell cycle arrest, including Histone H2AX, ATM kinase and Chk2, p53 and several others. DNA double strand break repair involves recruitment of Ku 70/80 proteins to the damage site leading to activation DNA protein kinases. Micronucleus (MN) formation is a hallmark of genetic toxicity; as such, micronuclei are used as indicators of genotoxicity caused by drug candidates or environmental toxins.
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