Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions

摘要: DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. We analysed a panel of lung hyperplasias, all which retained wild-type p53 genes and had no signs gross chromosomal instability, found response, including histone H2AX Chk2 phosphorylation, accumulation, focal staining binding protein 1 (53BP1) apoptosis. Progression to carcinoma was associated with or 53BP1 decreased A response also observed dysplastic nevi skin xenografts, hyperplasia induced by overexpression growth factors. Both experimentally-induced hyperplasias showed allelic imbalance at loci that prone double-strand break formation when replication is compromised (common fragile sites). propose that, from its earliest stages, cancer development stress, leads breaks, genomic instability mutations.