ArticlePloS one2013
MSH3 mismatch repair protein regulates sensitivity to cytotoxic drugs and a histone deacetylase inhibitor in human colon carcinoma cells.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 44 citations in OpenAlex.
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- TBKBP1 induces capecitabine resistance through negative regulation of type I interferon pathway in triple-negative breast cancer.Oncogene · 2026Article
- Synthetic Integration of an FCS into Coronaviruses-Hype or an Unresolved Biorisk? An Integrative Analysis of DNA Repair, Cancer Research, Drug Development, and Escape Mutant Traits.Life (Basel, Switzerland) · 2026Article
- MutSβ protects common fragile sites by facilitating homology-directed repair at DNA double-strand breaks with secondary structures.Nucleic acids research · 2024Article
- Elevated MSH2 MSH3 expression interferes with DNA metabolism in vivo.Nucleic acids research · 2023Article
- Radiosensitizing Effects of Irinotecan versus Oxaliplatin Alone and in Combination with 5-Fluorouracil on Human Colorectal Cancer Cells.International journal of molecular sciences · 2023Article
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- The Genomic Landscape of Corticotroph Tumors: From Silent Adenomas to ACTH-Secreting Carcinomas.International journal of molecular sciences · 2022Article
- Review
- Olaparib-mediated enhancement of 5-fluorouracil cytotoxicity in mismatch repair deficient colorectal cancer cells.BMC cancer · 2021Article
- Coordinated roles of SLX4 and MutSβ in DNA repair and the maintenance of genome stability.Critical reviews in biochemistry and molecular biology · 2021Review
- Transcriptome of the Krushinsky-Molodkina Audiogenic Rat Strain and Identification of Possible Audiogenic Epilepsy-Associated Genes.Frontiers in molecular neuroscience · 2021Article
- DNA Mismatch Repair Gene Variants in Sporadic Solid Cancers.International journal of molecular sciences · 2020Review
- Esophageal cancer genetics in South Africa.Clinical and experimental gastroenterology · 2019Review
- Distinctive DNA mismatch repair and APC rare variants in African Americans with colorectal neoplasia.Oncotarget · 2017Article
- Inactivation of MSH3 by promoter methylation correlates with primary tumor stage in nasopharyngeal carcinoma.International journal of molecular medicine · 2017Article
- Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer.Oncotarget · 2017Article
- Role of Deficient Mismatch Repair in the Personalized Management of Colorectal Cancer.International journal of environmental research and public health · 2016Review
- Genomic Profiling in Gastrointestinal Cancer: Are We Ready To Use These Data to Make Treatment Decisions?The oncologist · 2015Article
- Role of mismatch repair proteins in the processing of cisplatin interstrand cross-links.DNA repair · 2015Article
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4 authors at 1 institution in 1 country.
Funding
Abstract
backgroundMSH3 is a DNA mismatch repair (MMR) gene that undergoes frequent somatic mutation in colorectal cancers (CRCs) with MMR deficiency. MSH3, together with MSH2, forms the MutSβ heteroduplex that interacts with interstrand cross-links induced by drugs such as cisplatin. To date, the impact of MSH3 on chemosensitivity is unknown.
methodsWe utilized isogenic HCT116 (MLH1-/MSH3-) cells where MLH1 is restored by transfer of chromosome 3 (HCT116+ch3) and also MSH3 by chromosome 5 (HCT116+3+5). We generated HCT116+3+5, SW480 (MLH1+/MSH3+) and SW48 (MLH1-/MSH3+) cells with shRNA knockdown of MSH3. Cells were treated with 5-fluorouracil (5-FU), SN-38, oxaliplatin, or the histone deacetylase (HDAC) inhibitor PCI-24781 and cell viability, clonogenic survival, DNA damage and apoptosis were analyzed.
resultsMSH3-deficient vs proficient CRC cells showed increased sensitivity to the irinotecan metabolite SN-38 and to oxaliplatin, but not 5-FU, as shown in assays for apoptosis and clonogenic survival. In contrast, suppression of MLH1 attenuated the cytotoxic effect of 5-FU, but did not alter sensitivity to SN-38 or oxaliplatin. The impact of MSH3 knockdown on chemosensitivity to SN-38 and oxaliplatin was maintained independent of MLH1 status. In MSH3-deficient vs proficient cells, SN-38 and oxaliplatin induced higher levels of phosphorylated histone H2AX and Chk2, and similar results were found in MLH1-proficient SW480 cells. MSH3-deficient vs proficient cells showed increased 53BP1 nuclear foci after irradiation, suggesting that MSH3 can regulate DNA double strand break (DSB) repair. We then utilized PCI-24781 that interferes with homologous recombination (HR) indicated by a reduction in Rad51 expression. The addition of PCI-24781 to oxaliplatin enhanced cytotoxicity to a greater extent compared to either drug alone.
conclusionMSH3 status can regulate the DNA damage response and extent of apoptosis induced by chemotherapy. The ability of MSH3 to regulate chemosensitivity was independent of MLH1 status. PCI-24781-mediated impairment of HR enhanced oxaliplatin sensitivity, suggesting that reduced DSB repair capacity may be contributory.
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