ATR-mediated mechanotrasduction at the nuclear envelope

ATR kinase is involved in maintaining genome integrity by ensuring replication fork stability and coordinating cell cycle progression with the DNA repair.

ATR is a developmentally essential gene and in humans and hypomorphic mutations in ATR gene have been linked to Seckel syndrome characterized by mental and growth retardation and microcephaly.

While the role of ATR in mediating DNA damage response has been extensively studied, the findings that it senses mechanical forces and translocates to the nuclear envelope (NE), coupled with preliminary data, suggest that this translocation is involved in nuclear mechanoadaptation.

However, the mechanism of ATR recruitment and activation at the NE, proteins that are recruited or phosphorylated by ATR and the physiological relevance of ATR in a living organism, remain unknown.

We will thus use multidisciplinary approach, advanced molecular biology techniques, cutting edge imaging modalities and the vertebrate model Xenopus Laevis in order to address these questions.

Moreover, this proposal aims to identify the downstream consequences of this mechanical force-driven NE-ATR translocation, focusing on nuclear actin dynamics and epigenetic modification of histones.