Persistent mismatch repair deficiency following targeted correction of hMLH1
| Autor: | Michele Vitolo, Giancarlo Marra, Ben Ho Park, Kurtis E. Bachman, Katja Baerenfaller, M B Weiss |
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| Rok vydání: | 2006 |
| Předmět: |
Genetics
Cancer Research Base Sequence DNA Repair Base Pair Mismatch Genetic enhancement Blotting Western Nuclear Proteins Gene targeting Biology digestive system diseases Stop codon Exon Cell Line Tumor Cancer cell Humans Molecular Medicine DNA mismatch repair Carrier Proteins MutL Protein Homolog 1 Homologous recombination Molecular Biology Gene Adaptor Proteins Signal Transducing DNA Primers |
| Zdroj: | Cancer Gene Therapy. 14:98-104 |
| ISSN: | 1476-5500 0929-1903 |
| DOI: | 10.1038/sj.cgt.7700997 |
| Popis: | The use of gene therapy to correct mutated or lost gene function for the treatment of human cancers has been an active, yet problematic area of biomedical research. Many technical difficulties, including efficient tissue-specific delivery, integration site specificity and general toxicity, are being addressed. Little is known, however, about the genetic and phenotypic stability that accompanies a successful gene-specific targeting event in a cancer cell. This question was addressed following the creation of a colon cancer cell line in which a mutated hMLH1 gene was corrected via targeted homologous recombination. This correction resulted in the expression of wild-type hMLH1 protein, restoration of the hPMS2 protein and mismatch repair (MMR) proficiency. One of two hMLH1-corrected clones, however, was found to retain defects in MMR activity. These cells continued to express the corrected hMLH1 protein, but had lost expression of another MMR protein, hMSH6. DNA sequence analysis of the hMSH6 gene revealed biallelic expansions of a cytosine repeat region in exon 5 that result in frameshifts leading to premature stop codons. These findings suggest that, similar to acquired drug resistance, the presence of genetically heterogeneous cancer cell populations or acquisition of compensatory mutations can result in 'resistance' to gene replacement therapy. |
| Databáze: | OpenAIRE |
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