MicroRNA-138 modulates DNA damage response by repressing histone H2AX expression.

Abstract

Precise regulation of DNA damage response is crucial for cellular survival after DNA damage, and its abrogation often results in genomic instability in cancer. Phosphorylated histone H2AX (γH2AX) forms nuclear foci at sites of DNA damage and facilitates DNA damage response and repair. MicroRNAs (miRNA) are short, nonprotein-encoding RNA molecules, which posttranscriptionally regulate gene expression by repressing translation of and/or degrading mRNA. How miRNAs modulate DNA damage response is largely unknown. In this study, we developed a cell-based screening assay using ionizing radiation (IR)-induced γH2AX foci formation in a human osteosarcoma cell line, U2OS, as the readout. By screening a library of human miRNA mimics, we identified several miRNAs that inhibited γH2AX foci formation. Among them, miR-138 directly targeted the histone H2AX 3'-untranslated region, reduced histone H2AX expression, and induced chromosomal instability after DNA damage. Overexpression of miR-138 inhibited homologous recombination and enhanced cellular sensitivity to multiple DNA-damaging agents (cisplatin, camptothecin, and IR). Reintroduction of histone H2AX in miR-138 overexpressing cells attenuated miR-138-mediated sensitization to cisplatin and camptothecin. Our study suggests that miR-138 is an important regulator of genomic stability and a potential therapeutic agent to improve the efficacy of radiotherapy and chemotherapy with DNA-damaging agents.

• Authors: Yemin Wang, Jen-Wei Huang, Ming Li, Webster K Cavenee, Patrick S Mitchell, Xiaofeng Zhou, Muneesh Tewari, Frank B Furnari, Toshiyasu Taniguchi
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 9 Issue 8 Pg. 1100-11 (Aug 2011) ISSN: 1557-3125 [Electronic] United States
• PMID: 21693595 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• H1-10 protein, human
• MIRN138 microRNA, human
• MicroRNAs
• Nuclear Proteins
• RNA-Binding Proteins
• Cisplatin
• Camptothecin

Topics

• Camptothecin (pharmacology)
• Cell Cycle (drug effects, radiation effects)
• Cell Line
• Cell Line, Tumor
• Cell Survival (drug effects, radiation effects)
• Cisplatin (pharmacology)
• DNA Damage (radiation effects)
• DNA-Binding Proteins
• Gene Expression Regulation, Neoplastic
• Genomic Instability (genetics)
• HeLa Cells
• Humans
• MicroRNAs (genetics, metabolism)
• Neoplasms (metabolism)
• Nuclear Proteins (genetics, metabolism)
• RNA-Binding Proteins
• Radiation, Ionizing
• Stress, Physiological