Disease relevance of Pms2

• Interestingly, Pms2-deficient males display sterility associated with abnormal chromosome pairing in meiosis [1].
• Mice null for the Pms2 mismatch repair (MMR) gene exhibit a predisposition to lymphoma, microsatellite repeat instability, and failure of spermatogenesis [2].
• In addition, although Mlh1-/- mice also develop small intestinal adenomas and adenocarcinomas, Pms2-/- animals remain free of such tumors [3].
• DNA mismatch repair is important because of its role in maintaining genomic integrity and its association with hereditary non-polyposis colon cancer (HNPCC) [4].
• Mismatch repair (MMR) deficiency, which underlies hereditary nonpolyposis colorectal cancer, has recently been linked to a number of sporadic human cancers as well [5].

High impact information on Pms2

• Mice that are deficient in either the Pms2 or Msh2 DNA mismatch repair genes have microsatellite instability and a predisposition to tumours [1].
• Mice homozygous for a disrupted allele of the mismatch repair gene Pms2 have a mutator phenotype [6].
• Mismatch repair deficiency interferes with the accumulation of mutations in chronically stimulated B cells and not with the hypermutation process [7].
• By contrast, 23% of junctions from Mlh1- and Pms2-deficient cells occurred at unusually long stretches of microhomology [8].
• DNA mismatch repair in mammals: role in disease and meiosis [9].

Biological context of Pms2

• Previous nucleotide sequence analyses of switch recombination junctions indicated that the roles of Msh2 and the MutL homologues, Mlh1 and Pms2, differ [10].
• However, certain changes in mutation patterns and frequency of point mutations were observed in Msh2 (MutS homologue) and Pms2 (MutL homologue) MMR-deficient mice (for review see Kim, N., and U. Storb. 1998. J. Exp. Med. 187:1729-1733) [11].
• The data indicate that MMR proteins are directly involved in class switching and that the role of Msh2 differs from that of Mlh1 and Pms2 [8].
• The data also suggest a mechanistic basis for the more severe mismatch repair-related phenotypes and cancer susceptibility in Mlh1- versus Mlh3- or Pms2-deficient mice [12].
• However, when compared with Msh2(-/-) mice, lacI and cII mutants from Pms2-deficient mice revealed an increased proportion of +/-1 bp frameshift mutations and a corresponding decrease in transversion mutations [13].

Anatomical context of Pms2

• The data demonstrate clear differences in the sequences of switch junctions in wild-type B cells in comparison with Msh2-, Mlh1-, and Pms2-deficient B cells [8].
• Here, we extend these studies to the MutL homologues (MLH) Mlh1 and Pms2 by analysing the apoptotic response within the small intestine of gene targeted strains [14].
• Cells with either p53 or Pms2 separately disrupted showed reduced levels of apoptosis after IR in comparison with wild type, but the double null cells showed even lower levels, consistent with nonoverlapping roles for p53 and PMS2 in the X-ray response [15].
• In comparison to wild-type cell lines from related mice, the Pms2-, Mlh1-, or Msh2-nullizygous cell lines were found to exhibit higher levels of clonogenic survival following exposure to ionizing radiation [16].
• In transformed cell lines established from the primary cells at early passage, similar differences in the apoptotic response to IR were seen, and clonogenic survival assays following low dose rate IR further showed that nullizygosity for Pms2 confers increased survival on cells in both wild-type and p53 null backgrounds [15].

Associations of Pms2 with chemical compounds

• We show that treatment with temozolomide or 10mg/kg NMNU significantly increases mutation in both the Mlh1 and Pms2 mutant mice [14].
• Similarly, we observed a cisplatin-induced G2 arrest in immortalized MMR deficient (Mlh1(-/-) and Pms2(-/-)) and WT MEFs. p53 deficient primary MEFs (p53(-/-)) exhibited both a clear G2 arrest and an increase in cells with a DNA content of 8N in response to cisplatin [17].
• Although the K435 cells were as resistant to 6-thioguanine and cisplatin as Pms2 and Mlh1 null kidney cells, they were hypersensitive to MNNG [18].
• DNA mismatch repair deficiency stimulates N-ethyl-N-nitrosourea-induced mutagenesis and lymphomagenesis [19].
• Mismatch repair in methylated DNA. Structure and activity of the mismatch-specific thymine glycosylase domain of methyl-CpG-binding protein MBD4 [20].

Other interactions of Pms2

• Mutations of three of the four MutL homologues (Mlh1, Mlh3, and Pms2) result in meiotic defects [21].
• Therefore, hypermutation was studied in mice deficient for either the DNA nucleotide excision repair gene Xpa or the mismatch repair gene Pms2 [22].
• Loss of heterozygosity and point mutation at Aprt locus in T cells and fibroblasts of Pms2-/- mice [2].
• We conclude that Pms2-deficiency does not result in an amplification of the H-ras codon 61 CAA-->AAA mutational response induced by 4-ABP [23].
• Additional work demonstrated that growth of the Pms2 null cells in antioxidant containing medium reduced the rate of the A:T --> G:C mutations [24].

Analytical, diagnostic and therapeutic context of Pms2

• Mice rendered deficient in either Mlh1 or Pms2 as a result of gene targeting are prone to tumorigenesis, particularly, lymphomas [3].

References