ATM Modulates Nuclear Mechanics by Regulating Lamin A Levels
Pragya Shah1, Connor W McGuigan1, Svea Cheng1
1Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, United States.
Abstract:
Ataxia-telangiectasia mutated (ATM) is one of the three main apical kinases at the crux of DNA damage response and repair in mammalian cells. ATM activates a cascade of downstream effector proteins to regulate DNA repair and cell cycle checkpoints in response to DNA double-strand breaks. While ATM is predominantly known for its role in DNA damage response and repair, new roles of ATM have recently begun to emerge, such as in regulating oxidative stress or metabolic pathways. Here, we report the surprising discovery that ATM inhibition and deletion lead to reduced expression of the nuclear envelope protein lamin A. Lamins are nuclear intermediate filaments that modulate nuclear shape, structure, and stiffness. Accordingly, inhibition or deletion of ATM resulted in increased nuclear deformability and enhanced cell migration through confined spaces, which requires substantial nuclear deformation. These findings point to a novel connection between ATM and lamin A and may have broad implications for cells with ATM mutations-as found in patients suffering from Ataxia Telangiectasia and many human cancers-which could lead to enhanced cell migration and increased metastatic potential.
Insights
Ataxia-telangiectasia mutated (ATM) kinase inhibition reduces lamin A, increasing nuclear deformability and cell migration. This ATM-lamin A link may enhance cancer cell metastasis.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Ataxia-telangiectasia mutated (ATM) is a key kinase in DNA damage response.
- Emerging roles for ATM include regulation of oxidative stress and metabolism.
- ATM mutations are linked to Ataxia Telangiectasia and various cancers.
Purpose of the Study:
- To investigate novel functions of ATM beyond DNA repair.
- To explore the impact of ATM inhibition or deletion on cellular mechanics.
- To identify potential therapeutic targets for ATM-mutated cancers.
Main Methods:
- Utilized ATM inhibition and gene deletion models.
- Assessed expression levels of nuclear envelope proteins, specifically lamin A.
- Measured nuclear deformability and cell migration through confined environments.
Main Results:
- ATM inhibition and deletion significantly reduced lamin A expression.
- ATM-deficient cells exhibited increased nuclear deformability.
- Enhanced cell migration through restrictive spaces was observed in ATM-inhibited/deleted cells.
Conclusions:
- A novel link between ATM and lamin A expression was discovered.
- ATM regulates nuclear stiffness and cell migration via lamin A.
- This finding has implications for understanding and treating ATM-mutated cancers, potentially impacting metastatic potential.
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