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The cytoskeleton adaptor protein ankyrin-1 is upregulated by p53 following DNA damage and alters cell migration
A E Hall1, W-T Lu1, J D Godfrey1
1Medical Research Council (MRC), Toxicology Unit, Leicester, UK.
Abstract:
The integrity of the genome is maintained by a host of surveillance and repair mechanisms that are pivotal for cellular function. The tumour suppressor protein p53 is a major component of the DNA damage response pathway and plays a vital role in the maintenance of cell-cycle checkpoints. Here we show that a microRNA, miR-486, and its host gene ankyrin-1 (ANK1) are induced by p53 following DNA damage. Strikingly, the cytoskeleton adaptor protein ankyrin-1 was induced over 80-fold following DNA damage. ANK1 is upregulated in response to a variety of DNA damage agents in a range of cell types. We demonstrate that miR-486-5p is involved in controlling G1/S transition following DNA damage, whereas the induction of the ankyrin-1 protein alters the structure of the actin cytoskeleton and sustains limited cell migration during DNA damage. Importantly, we found that higher ANK1 expression correlates with decreased survival in cancer patients. Thus, these observations highlight ANK1 as an important effector downstream of the p53 pathway.
Insights
The tumor suppressor p53 activates microRNA miR-486 and ankyrin-1 (ANK1) after DNA damage. ANK1 protein levels increase significantly, impacting cell migration and survival in cancer patients.
Area of Science:
- Molecular biology
- Cellular biology
- Genomics
Background:
- Genome integrity is crucial for cellular function, maintained by surveillance and repair mechanisms.
- The tumor suppressor protein p53 is central to DNA damage response and cell-cycle control.
- MicroRNAs (miRNAs) and their host genes play significant roles in cellular processes.
Purpose of the Study:
- To investigate the downstream targets of p53 following DNA damage.
- To elucidate the role of miR-486 and its host gene ankyrin-1 (ANK1) in the DNA damage response.
- To explore the clinical relevance of ANK1 in cancer.
Main Methods:
- Induction of DNA damage in various cell types.
- Quantitative analysis of miR-486 and ANK1 expression.
- Assessment of cell-cycle progression (G1/S transition).
- Microscopy to analyze actin cytoskeleton structure and cell migration.
- Correlation analysis of ANK1 expression with patient survival data.
Main Results:
- p53 induces miR-486 and its host gene ankyrin-1 (ANK1) upon DNA damage.
- ANK1 protein expression increased over 80-fold, and ANK1 is upregulated by diverse DNA damaging agents.
- miR-486-5p influences G1/S cell-cycle transition post-DNA damage.
- ANK1 alters actin cytoskeleton structure, supporting limited cell migration during DNA damage.
- Elevated ANK1 expression is associated with poorer survival rates in cancer patients.
Conclusions:
- ANK1 is a significant effector downstream of the p53 pathway in response to DNA damage.
- miR-486 and ANK1 play distinct but coordinated roles in the cellular response to DNA damage.
- ANK1 represents a potential prognostic biomarker in cancer.
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