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ATM-dependent activation of the gene encoding MAP kinase phosphatase 5 by radiomimetic DNA damage
Anat Bar-Shira1, Sharon Rashi-Elkeles, Liat Zlochover
1The David and Inez Myers Laboratory for Genetic Research, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Abstract:
Cellular responses to DNA damage are mediated by an extensive network of signaling pathways. The ATM protein kinase is a master regulator of the response to double-strand breaks (DSBs), the most cytotoxic DNA lesion caused by ionizing radiation. ATM is the protein missing or inactive in patients with the pleiotropic genetic disorder ataxia-telangiectasia (A-T). A major response to DNA damage is altered expression of numerous genes. While studying gene expression in control and A-T cells following treatment with the radiomimetic chemical neocarzinostatin (NCS), we identified an expressed sequence tag that represented a gene that was induced by DSBs in an ATM-dependent manner. The corresponding cDNA encoded a dual specificity phosphatase of the MAP kinase phosphatase family, MKP-5. MKP-5 dephosphorylates and inactivates the stress-activated MAP kinases JNK and p38. The phosphorylation-dephosphorylation cycle of JNK and p38 by NCS was attenuated in A-T cells. Thus, ATM modulates this cycle in response to DSBs. These results further highlight ATM as a link between the DNA damage response and major signaling pathways involved in proliferative and apoptotic processes.
Insights
The ATM protein kinase regulates cellular responses to DNA double-strand breaks (DSBs). Researchers identified MKP-5, a gene induced by DSBs in an ATM-dependent manner, highlighting ATM
Area of Science:
- Molecular biology
- Cellular signaling
- DNA damage response
Background:
- Cellular responses to DNA damage involve complex signaling networks.
- ATM protein kinase is crucial for managing double-strand breaks (DSBs), the most lethal DNA lesions.
- Ataxia-telangiectasia (A-T) is a genetic disorder characterized by ATM deficiency.
Purpose of the Study:
- To investigate gene expression changes in response to DNA damage.
- To identify genes regulated by ATM in response to double-strand breaks (DSBs).
- To elucidate the role of ATM in the modulation of stress-activated MAP kinases.
Main Methods:
- Treatment of control and A-T cells with neocarzinostatin (NCS) to induce DSBs.
- Gene expression analysis using expressed sequence tags.
- Identification and characterization of the MKP-5 gene.
- Analysis of MAP kinase (JNK and p38) phosphorylation-dephosphorylation cycles.
Main Results:
- An ATM-dependent gene, MKP-5, was identified and induced by DSBs.
- MKP-5 encodes a dual specificity phosphatase that dephosphorylates and inactivates JNK and p38.
- The phosphorylation-dephosphorylation cycle of JNK and p38 was attenuated in A-T cells, indicating ATM's role.
Conclusions:
- ATM plays a critical role in modulating the JNK and p38 signaling pathways in response to DSBs.
- MKP-5 is a key component of the ATM-dependent DNA damage response pathway.
- These findings underscore ATM's function as a bridge between DNA damage signaling and cellular processes like proliferation and apoptosis.