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ATM-mediated response to DNA double strand breaks in human neurons derived from stem cells
Sharon Biton1, Michal Gropp, Pavel Itsykson
1David and Inez Myers Laboratory for Genetic Research, Department of Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Abstract:
Ataxia-telangiectasia (A-T) is a multi-system genomic instability syndrome that is caused by loss or inactivation of the ATM protein kinase. ATM is largely nuclear in proliferating cells, and activates an extensive network of pathways in response to double strand breaks (DSBs) in the DNA by phosphorylating key proteins in these pathways. The prominent symptom of A-T is neuronal degeneration, making the elucidation of ATM's functions in neurons essential to understanding the disease. It has been suggested that ATM is cytoplasmic in neurons and functions in processes that are not associated with the DNA damage response. Recently we showed that in human neuron-like cells obtained by in vitro differentiation of neuroblastomas, ATM was largely nuclear and mediated the DSB response as in proliferating cells. We have now extended these studies to two additional model systems: neurons derived from human embryonic stem cells, and cortical neurons derived from neural stem cells. The results substantiate the notion that ATM is nuclear in human neurons and mediates the DSB response, the same as it does in proliferating cells. We present here unique and powerful model systems to further study the ATM-mediated network in neurons.
Insights
Ataxia-telangiectasia (A-T) involves ATM protein kinase dysfunction. Studies confirm ATM is nuclear in human neurons, mediating DNA double-strand break responses, similar to proliferating cells.
Area of Science:
- Genetics
- Neuroscience
- Cell Biology
Background:
- Ataxia-telangiectasia (A-T) is a genomic instability syndrome resulting from ATM protein kinase loss.
- ATM kinase is crucial for DNA double-strand break (DSB) response in proliferating cells.
- Neuronal degeneration in A-T highlights the need to understand ATM's role in neurons.
Purpose of the Study:
- To investigate the localization and function of ATM protein kinase in human neurons.
- To determine if ATM mediates DNA damage response in neurons as it does in proliferating cells.
- To validate novel human neuronal models for studying ATM in A-T.
Main Methods:
- Utilized human neuroblastoma-derived cells, human embryonic stem cell-derived neurons, and neural stem cell-derived cortical neurons.
- Assessed ATM localization (nuclear vs. cytoplasmic) in differentiated neuronal models.
- Evaluated ATM's role in mediating the DNA double-strand break (DSB) response in these neuronal systems.
Main Results:
- Confirmed ATM is predominantly nuclear in human neurons across multiple model systems.
- Demonstrated that ATM mediates the DNA double-strand break (DSB) response in human neurons.
- Established that ATM functions similarly in neurons as in proliferating cells regarding DSB response.
Conclusions:
- ATM plays a significant nuclear role in human neurons, participating in DNA damage response.
- These findings challenge previous suggestions of cytoplasmic ATM function in neurons.
- Developed robust human neuronal models for further investigation of ATM-mediated pathways in A-T pathogenesis.
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