ArticleMolecular and cellular biology2003
Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells.
Article in Molecular and cellular biology, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 136 papers.
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Who cites it
136 citing papers in PubMed, 274 citations in OpenAlex.
- Oligometastatic Prostate Cancer: Clues from an N-of-1.Journal of clinical medicine · 2026Article
- Aberrant cytoplasmic localization of MLH1 characterizes a cell population that seeds breast cancer recurrence.Nature communications · 2025Article
- Mismatch Repair as a Dynamic and Clinically Actionable Vulnerability in Cancer.Cancer research · 2025Review
- Convergent Genetic Adaptation in Human Tumors Developed Under Systemic Hypoxia and in Populations Living at High Altitudes.Cancer discovery · 2025Article
- Tumour hypoxia in driving genomic instability and tumour evolution.Nature reviews. Cancer · 2025Review
- BHLHE41, a transcriptional repressor involved in physiological processes and tumor development.Cellular oncology (Dordrecht, Netherlands) · 2025Review
- Targeting the epigenome and tumor heterogeneity: advances in immunotherapy for chemoresistant metastatic colorectal cancer.Frontiers in immunology · 2025Review
- ECM Proteins Nidogen-1 and Decorin Restore Functionality of Human Islets of Langerhans upon Hypoxic Conditions.Advanced healthcare materials · 2025Article
- Article
- Platinum chemotherapeutic-induced oxidative stress affects the transcriptional response of DNA repair genes in murine mesenchymal stem cells.American journal of stem cells · 2025Article
- Tumour response to hypoxia: understanding the hypoxic tumour microenvironment to improve treatment outcome in solid tumours.Frontiers in oncology · 2024Review
- MicroRNA-367-3p directly targets RAB23 and inhibits proliferation, migration and invasion of bladder cancer cells and increases cisplatin sensitivity.Journal of cancer research and clinical oncology · 2023Article
- Sleep Disorder Kleine-Levin Syndrome (KLS) Joins the List of Polygenic Brain Disorders Associated with Obstetric Complications.Cellular and molecular neurobiology · 2023Review
- Hypoxia: syndicating triple negative breast cancer against various therapeutic regimens.Frontiers in oncology · 2023Review
- Differential expression of checkpoint markers in the normoxic and hypoxic microenvironment of glioblastomas.Brain pathology (Zurich, Switzerland) · 2023Article
- Review
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- Stress-Induced Mutagenesis, Gambler Cells, and Stealth Targeting Antibiotic-Induced Evolution.mBio · 2022Review
- Glioblastoma Microenvironment: From an Inviolable Defense to a Therapeutic Chance.Frontiers in oncology · 2022Review
- Prediction of immunotherapy efficacy and immunomodulatory role of hypoxia in colorectal cancer.Therapeutic advances in medical oncology · 2022Review
76 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
The hypoxic tumor microenvironment has been shown to contribute to genetic instability. As one possible mechanism for this effect, we report that expression of the DNA mismatch repair (MMR) gene Mlh1 is specifically reduced in mammalian cells under hypoxia, whereas expression of other MMR genes, including Msh2, Msh6, and Pms2, is not altered at the mRNA level. However, levels of the PMS2 protein are reduced, consistent with destabilization of PMS2 in the absence of its heterodimer partner, MLH1. The hypoxia-induced reduction in Mlh1 mRNA was prevented by the histone deacetylase inhibitor trichostatin A, suggesting that hypoxia causes decreased Mlh1 transcription via histone deacetylation. In addition, treatment of cells with the iron chelator desferrioxamine also reduced MLH1 and PMS2 levels, in keeping with low oxygen tension being the stress signal that provokes the altered MMR gene expression. Functional MMR deficiency under hypoxia was detected as induced instability of a (CA)(29) dinucleotide repeat and by increased mutagenesis in a chromosomal reporter gene. These results identify a potential new pathway of genetic instability in cancer: hypoxia-induced reduction in the expression of key MMR proteins. In addition, this stress-induced genetic instability may represent a conceptual parallel to the pathway of stationary-phase mutagenesis seen in bacteria.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.