がん抑制遺伝子p53の組み換え修復を介した遺伝的安定化機構 : 第29回大会受賞講演

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Chromosomal double strand breaks (DSB) occurring in mammalian cells can initiate genomic instability and their misrepairs result in chromosomal deletion, amplification, or translocation, common findings in human tumors. The tumor suppressor protein p53 is involved in maintaining genomic stability. We demonstrate here that the deficiency of wild-type p53 protein may allow unrepaired DSB to initiate chromosomal instability. The human lymphoblastoid cell line TK6-E6 was established by transfection with HPV16 E6 cDNA into parental TK6 cells via a retroviral vector. Abrogation of p53 function by E6 resulted in an increase in the spontaneous mutation frequencies at the heterozygous thymidine kinase (tk) locus. Almost all TK-deficient mutants from TK6-E6 cells exhibited loss of heterozygosity (LOH) with the hemizygous tk allele. LOH analysis with microsatellite loci spanning the long arm of chromosome 17, which harbors the tk locus, revealed that LOH extended over half of 17q toward the terminal end. Cytogenetic analysis of LOH mutants by chromosome painting indicated a mosaic of chromosomal aberrations involving chromosome 17, in which partial chromosome deletions, amplifications and multiple translocations appeared heterogeneously in a single mutant. We speculate that spontaneous DSB triggers the breakage-fusion-bridge cycle leading to such multiple chromosome aberrations. In contrast, no chromosomal alterations were observed in TK-deficient mutants from TK6-20C cells expressing wild-type p53. In wild-type p53 cells, spontaneous DSB appear to be promptly repaired through recombination between homologous chromosomes. These results support a model in which p53 protein contributes to the maintenance of genomic integrity through recombinational repair.
日本環境変異原学会の論文
2001-06-30

がん抑制遺伝子p53の組み換え修復を介した遺伝的安定化機構 : 第29回大会受賞講演

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