A hPMS2 mutant cell line is defective in strand-specific mismatch repair.
Human cells contain several homologs of the bacterial mutL gene required for mismatch repair, including a gene on chromosome 7 designated hPMS2. We have identified an endometrial carcinoma cell line, HEC-1-A, that has a C-->T mutation in hPMS2 that generates a nonsense codon and yields a protein truncated at the C terminus. No wild-type gene or gene product was detected. The missing amino acids in hPMS2 are highly conserved among PMS homologs, suggesting that they may be critical for function. In support of this, extracts of HEC-1-A cells are defective in repairing a variety of mismatched substrates. Moreover, di-, tri-, and tetranucleotide repeated sequences are highly unstable in single cell clones of HEC-1-A cells, and HEC-1-A cells are resistant to killing by N-methyl-N'-nitro-N-nitrosoguanidine. The results provide strong experimental support for the involvement of the hPMS2 gene product in mismatch repair in human cells and support the concept that a defective hPMS2 gene may lead to predisposition to certain forms of cancer.
Risinger
J I
JI
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Umar
A
A
Barrett
J C
JC
Kunkel
T A
TA
D000251:Adenosine Triphosphatases; D001483:Base Sequence; D002277:Carcinoma / Q000209:etiology / Q000235:genetics*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes; D004276:DNA, Satellite / Q000235:genetics; D004268:DNA-Binding Proteins; D016889:Endometrial Neoplasms / Q000209:etiology / Q000235:genetics*; D005260:Female; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D000070976:Mismatch Repair Endonuclease PMS2; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D014407:Tumor Cells, Cultured
D004276:DNA, Satellite; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D008769:Methylnitronitrosoguanidine; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes