MechanoATR · ATR-mediated mechanotrasduction at the nuclear envelope

ATR-mediated mechanotrasduction at the nuclear envelope

Cells can sense and respond to mechanical forces, translating these cues into coordinated gene expression changes that impact processes such as cell differentiation, tissue renewal, and homeostasis. ATR kinase is essential for maintaining genome integrity by stabilizing replication forks and coordinating DNA repair with cell cycle progression. While the role of ATR in mediating the DNA damage response is well-established, recent findings suggest that ATR also senses mechanical forces and translocates to the nuclear envelope (NE), where it plays a role in nuclear mechanoadaptation. Understanding how ATR mediates nuclear responses to mechanical forces can lead to improved treatments for conditions where NE instability and genome integrity are compromised. This includes not only laminopathies but also cancer, aging-related diseases, and other genetic disorders. Our study aimed to elucidate the mechanism by which ATR responds to mechanical forces and the downstream effects of this response on nuclear integrity. Using advanced molecular biology techniques, cutting-edge imaging modalities, and the vertebrate model Xenopus laevis, we will investigate the downstream consequences of NE-ATR translocation, focusing on nuclear actin dynamics. Our findings reveal a novel mechanotransduction pathway where ATR, upon sensing mechanical forces, translocates to the NE and phosphorylates RASSF1A. This phosphorylation event regulates nuclear actin . This ATR/RASSF1A pathway represents a crucial mechanism by which cells maintain genome integrity and adapt to mechanical stress, with potential implications for understanding diseases characterized by genome instability and impaired mechanotransduction.

Data: CORDIS, © European Union