Heterozygosity for p53 promotes microsatellite instability and tumorigenesis on a Msh2 deficient background

Abstract

In colorectal tumorigenesis, loss of function of the mismatch repair genes is closely associated with genomic instability at the nucleotide level whereas p53 deficiency has been linked with gross chromosomal instability. We have addressed the contribution of these two forms of genetic instability to tumorigenesis using mice mutant for Msh2 and p53. As previously reported, deficiency of both genes leads to rapid lymphomagenesis Here we show that heterozygosity for p53 also markedly reduces survival on an Msh2 null background. We characterized the patterns of genomic instability in a small set of tumours and showed that, as predicted p53 deficiency predisposes to aneuploidy and Msh2 deficiency leads to microsatellite instability (MSI). However, heterozygosity for p53 in the absence of Msh2 resulted in increased MSI and not aneuploidy. This implied role for p53 in modulating MSI was confirmed using a large cohort of primary fibroblast clones. The differences observed were highly significant (P50.01) in both the fibroblast clones (which all retained p53 functionality) and the tumours, a proportion of which retained p53 functionality. Our results therefore demonstrate a dose sensitive role for p53 in the maintenance of genomic integrity at the nucleotide level.

MBD4 deficiency does not increase mutation or accelerate tumorigenesis in mice lacking MMR

“…Given previous reports that one mutation of Mbd4 can accelerate MSI, tumours were assessed for instability at four microsatellite loci Toft et al, 2002). Four microsatellite loci were chosen for analysis: D1Mit4, D7Mit17, D10Mit2 and D14Mit15.…”

MBD2 deficiency does not accelerate p53 mediated lymphomagenesis

“…Mbd2 and p53 mutant animals were derived from a colony segregating for Ola/129 and C57BL6J genomes, which had been backcrossed three generations onto the C57BL6J background and so were predominantly (87.5%) C57/BL6J. Mice were genotyped by PCR as previously described (Toft et al, 2002;Sansom et al, 2003). Cohorts of at least 18 mice were monitored and harvested when they exhibited symptoms of disease.…”

Wild-type p53 stimulates homologous recombination upon sequence-specific binding to the ribosomal gene cluster repeat

“…The orientation of the RGC and the mutated RGC motif was the same within all three SV40 genomes. Third, to challenge a potential recombination regulatory role of p53 directed toward repetitive DNA sequences in general (Ahrendt et al, 2000;Gebow et al, 2000;Danaee et al, 2002;Toft et al, 2002), we inserted a triplet repeat consisting of 98 CTG copies that causes enhancement of intermolecular recombination in an Escherichia coli plasmid system (Bowater et al, 1996;Pluciennik et al, 2002).…”

“…Moreover, microsatellite instabilities at tetranucleotide repeats were found to be associated with p53 mutations in skin, bladder, and lung cancer (Ahrendt et al, 2000;Danaee et al, 2002). Finally, on the basis of examinations in thymic lymphomas from MSH2/p53 intercrossed mice, it was proposed that p53 modulates microsatellite instabilities and becomes essential to this process after loss of MSH2 (Toft et al, 2002). In this study, a threefold recombination enhancement was conferred by the (CTG) 98 microsatellite repeat in the parental line without wtp53, which is consistent with previous studies that suggested that homologous recombination is the mechanism underlying instabilities at this triplet repeat within the myotonic dystrophy locus (Richard and Paques, 2000).…”