Germline mutations at microsatellite loci in homozygous and heterozygous mutants for mismatch repair and PCNA genes in Drosophila.
Microsatellite instability (MSI) is a phenotype associated with the deficient repair of replication errors. Replication errors persist in defective mismatch repair (MMR) conditions, although alterations in components of the replication machinery, such as the proliferating cell nuclear antigen (PCNA) factor, could also increase the replication errors; therefore, MSI is expected in both situations. It also seems that heterozygous individuals for MMR genes have a high risk of cancer, as in the case of human non-polyposis colon carcinoma (HNPCC), characterised by MSI. Thus, here we investigate the effect of heterozygosity for a Msh2-null allele or for altered PCNA alleles, on the stability of microsatellite sequences. The study was carried out in Drosophila germ cells analysing the progeny of individual crosses. We found that one Msh2 disrupted allele is sufficient to produce MSI in germ cells. Although the MSI in Msh2(-/+) individuals was in the same order of magnitude as in Msh2(-/-) individuals, the former manifested a MSI that was four-fold lower. To a lesser extent, PCNA homozygous and heterozygous mutants also show MSI in the germline, which reveals the importance of DNA replication factors to maintain genomic stability in vivo. Furthermore, the high MSI found both in heterozygous Msh2 and PCNA mutants suggests a high degree of genomic instability in individuals bearing a mutant allele of these genes, which could have important implications in cancer susceptibility.
Baida
A
A
Grup de Mutagènesi, Unitat de Genètica, Departament de Genètica i de Microbiologia, Edifici Cn, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
López
A
A
Marcos
R
R
Velázquez
A
A
D000818:Animals; D020137:Base Pair Mismatch / Q000235:genetics*; D003433:Crosses, Genetic; D004260:DNA Repair; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics*; D042822:Genomic Instability; D018095:Germ-Line Mutation / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics
D029721:Drosophila Proteins; D018809:Proliferating Cell Nuclear Antigen; D012097:Repressor Proteins; D015534:Trans-Activators; C102933:tin protein, Drosophila