Requirement of wild-type p53 protein for maintenance of chromosomal integrity

Abstract

Chromosomal double‐strand breaks (DSBs) occurring in mammalian cells can initiate genomic instability, and their misrepairs result in chromosomal deletion, amplification, and translocation, common findings in human tumors. The tumor‐suppressor protein p53 is involved in maintaining genomic stability. In this study, we demonstrate that the deficiency of wild‐type p53 protein may allow unrepaired DSBs to initiate chromosomal instability. The human lymphoblastoid cell line TK6‐E6 was established by transfection with human papilloma virus 16 (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 but not at the hemizygous hypoxanthine phosphoribosyl transferase (HPRT) 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, showed 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 DSBs trigger 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 DSBs 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. Mol. Carcinog. 28:203–214, 2000. © 2000 Wiley‐Liss, Inc.

Role of genetic background in induced instability

“…An extensive characterization of the positive correlation between reduced levels of normal TP53 and several instability end points has been demonstrated in human cell lines (Honma et al, 1997(Honma et al, , 2000Schwartz et al, 2001;Leger and Drobetsky, 2002). Further work using unstable clones from the human chromosome 4 hamster-hybrid system (GM10115) has shown that the radiosensitive phenotype was related to the efficiency of DNA repair (Limoli et al, 2001), supporting earlier results in GADD45 À/À mice.…”

Epstein–Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity

“…In addition, p53 plays an important role in maintaining genomic stability (Harvey et al, 1993;Albrechtsen et al, 1999;Janus et al, 1999;Burt et al, 2000;Honma et al, 2000;Overholtzer et al, 2003). Since we demonstrated that LMP1 could repress DNA repair in both p53-wild-type and p53-deficient human epithelial cells (Liu et al, 2004), it seems that LMP1 may repress DNA repair in a p53-independent manner.…”

Integrins regulate the apoptotic response to DNA damage through modulation of p53

“…p53 is critical for maintaining integrity of the genome (34,35), and hence decreased p53 in suspended cells could cause genetic instability. Treatment with radiation or chemotherapy then could lead to accumulation of mutations at an elevated rate.…”