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An Inducible, Isogenic Cancer Cell Line System for Targeting the State of Mismatch Repair Deficiency

Bailis, Julie M. and Gordon, Marcia L. and Gurgel, Jesse L. and Komor, Alexis C. and Barton, Jacqueline K. and Kirsch, Ilan R. (2013) An Inducible, Isogenic Cancer Cell Line System for Targeting the State of Mismatch Repair Deficiency. PLoS ONE, 8 (10). Art. No. e78726. ISSN 1932-6203. PMCID PMC3812133. doi:10.1371/journal.pone.0078726. https://resolver.caltech.edu/CaltechAUTHORS:20131205-114027493

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Abstract

The DNA mismatch repair system (MMR) maintains genome stability through recognition and repair of single-base mismatches and small insertion-deletion loops. Inactivation of the MMR pathway causes microsatellite instability and the accumulation of genomic mutations that can cause or contribute to cancer. In fact, 10-20% of certain solid and hematologic cancers are MMR-deficient. MMR-deficient cancers do not respond to some standard of care chemotherapeutics because of presumed increased tolerance of DNA damage, highlighting the need for novel therapeutic drugs. Toward this goal, we generated isogenic cancer cell lines for direct comparison of MMR-proficient and MMR-deficient cells. We engineered NCI-H23 lung adenocarcinoma cells to contain a doxycycline-inducible shRNA designed to suppress the expression of the mismatch repair gene MLH1, and compared single cell subclones that were uninduced (MLH1-proficient) versus induced for the MLH1 shRNA (MLH1-deficient). Here we present the characterization of these MMR-inducible cell lines and validate a novel class of rhodium metalloinsertor compounds that differentially inhibit the proliferation of MMR-deficient cancer cells.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1371/journal.pone.0078726DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812133/PubMed CentralArticle
ORCID:
AuthorORCID
Barton, Jacqueline K.0000-0001-9883-1600
Additional Information:© 2013 Bailis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received June 24, 2013; Accepted September 17, 2013; Published October 29, 2013. The authors thank the NIH (GM33309 to J.K.B.) and NSF (fellowship to A.C.K.) for financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Julie Bailis, Marcia Gordon, Jesse Gurgel, and Ilan Kirsch are or were employees of Amgen, Inc. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. We thank Michael Damore (Amgen) for microarray analysis, and Oahn Hong (UCSD Cancer Center) for analysis of samples for microsatellite instability. Author Contributions: Conceived and designed the experiments: JMB JKB IRK. Performed the experiments: JMB MLG JLG. Analyzed the data: JMB ACK JKB IRK. Contributed reagents/materials/analysis tools: MLG JLG ACK. Wrote the manuscript: JMB IRK.
Funders:
Funding AgencyGrant Number
NIHGM33309
NSFUNSPECIFIED
Issue or Number:10
PubMed Central ID:PMC3812133
DOI:10.1371/journal.pone.0078726
Record Number:CaltechAUTHORS:20131205-114027493
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20131205-114027493
Official Citation:Bailis JM, Gordon ML, Gurgel JL, Komor AC, Barton JK, et al. (2013) An Inducible, Isogenic Cancer Cell Line System for Targeting the State of Mismatch Repair Deficiency. PLoS ONE 8(10): e78726. doi:10.1371/journal.pone.0078726
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:42858
Collection:CaltechAUTHORS
Deposited By: David McCaslin
Deposited On:05 Dec 2013 22:33
Last Modified:10 Nov 2021 16:29

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