Molecular processes of chromosome 9p21 deletions causing inactivation of the p16 tumor suppressor gene in human cancer: deduction from structural analysis of breakpoints for deletions.
Chromosome interstitial deletion (i.e., deletion of a chromosome segment in a chromosome arm) is a critical genetic event for the inactivation of tumor suppressor genes and activation of oncogenes leading to the carcinogenic conversion of human cells. The deletion at chromosome 9p21 removing the p16 tumor suppressor gene is a genetic alteration frequently observed in a variety of human cancers. Thus, structural analyses of breakpoints for p16 deletions in several kinds of human cancers have been performed to elucidate the molecular process of chromosome interstitial deletion consisting of formation of DNA double strand breaks (DSBs) and subsequent joining of DNA ends in human cells. The results indicated that DSBs triggering deletions in lymphoid leukemia are formed at a few defined sites by illegitimate action of the RAG protein complex, while DSBs in solid tumors are formed at unspecific sites by factors unidentified yet. In both types of tumors, the intra-nuclear architecture of chromatin was considered to affect the susceptibility of genomic segments of the p16 locus to DSBs. Broken DNA ends were joined by non-homologous end joining (NHEJ) repair in both types of tumors, however, microhomologies of DNA ends were preferentially utilized in the joining in solid tumors but not in lymphoid leukemia. The configuration of broken DNA ends as well as NHEJ activity in cells was thought to underlie the features of joining. Further structural analysis of other hot spots of chromosomal DNA breaks as well as the evaluation of the activity and specificity of NHEJ in human cells will elucidate the mechanisms of chromosome interstitial deletions in human cells.
Kohno
Takashi
T
Biology Division, National Cancer Center Research Institute, Tokyo, Japan. tkkohno@gan2.res.ncc.go.jp
Yokota
Jun
J
D001483:Base Sequence; D019457:Chromosome Breakage; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9; D004260:DNA Repair; D004273:DNA, Neoplasm; D019942:Genes, p16; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm