ATM Modulates Nuclear Mechanics by Regulating Lamin A Levels
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 01, 2022
- Source ID
- 10.3389/fcell.2022.875132
Entities
People
- Claire Vanpouille-Box
- Connor W. Mcguigan
- Jan Lammerding
- Pragya Shah
- Robert S. Weiss
- Sandra Demaria
- Svea Cheng
Organizations
- Congressionally Directed Medical Research Programs
- National Institutes of Health
- National Science Foundation