Navigation auf zora.uzh.ch

Search ZORA

ZORA (Zurich Open Repository and Archive)

DDOS: due to massive botnet requests against our ‘Advanced Search’ we have restricted access to UZH (local and VPN). Thank you for your understanding.

Persistent mismatch repair deficiency following targeted correction of hMLH1

Weiss, M B; Vitolo, M I; Baerenfaller, K; Marra, Giancarlo; Park, B H; Bachman, K E (2007). Persistent mismatch repair deficiency following targeted correction of hMLH1. Cancer Gene Therapy, 14(1):98-104.

Abstract

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.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Molecular Medicine
Life Sciences > Molecular Biology
Life Sciences > Cancer Research
Language:English
Date:2007
Deposited On:09 Aug 2010 10:57
Last Modified:04 Jun 2025 01:38
Publisher:Nature Publishing Group
ISSN:0929-1903
OA Status:Closed
Publisher DOI:https://doi.org/10.1038/sj.cgt.7700997
PubMed ID:17082796

Metadata Export

Statistics

Citations

Dimensions.ai Metrics
6 citations in Web of Science®
6 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

4 downloads since deposited on 09 Aug 2010
0 downloads since 12 months
Detailed statistics

Authors, Affiliations, Collaborations

Similar Publications