ATR MEDIATED REGULATION OF CELLULAR AND NUCLEAR PLASTICITY

Protein kinase ATR (Ataxia Telangiectasia and Rad3-related) is a key regulator of genomic integrity. In addition to its vital, well-understood role in maintaining replication fork stability, ATR is also involved in mediating mechanical stress response at the nuclear envelope preventing potential threats to the genome. Our data from sub-cellular distribution and interactome analysis of ATR suggests that ATR contributes to several cellular processes in multiple organelles such as mitochondria, actin cytoskeleton, Golgi and nuclear envelope. At the nuclear envelope ATR is present on both inner and outer nuclear membranes, on the nuclear pores and bound to perinuclear chromatin and to perinuclear actin fibers. In this study we show that ATR regulates nuclear membrane integrity by maintaining nuclear morphology and optimal membrane tension, by counteracting mechanical force imbalances at the NE and by coordinating nuclear events with nuclear and cell migration. We report a novel role of ATR in preventing and protecting nuclear envelope damage and DNA damage caused by mechanical constrains acting on the nucleus. Further we show that by maintaining nuclear envelope integrity ATR facilitates cell migration on 2D surfaces and by regulating nuclear membrane components and by limiting nuclear envelope damage it aids cell survival during confined 3D migrations. Loss of ATR dampens neuronal migration during development and cancer cells lacking ATR are inefficient in extravasation, do not survive circulation and fail to successfully metastasize into the host environment. Therefore, by promoting cell survival in altering mechanical microenvironment and during metastasis and invasion, ATR assists tumor development, suggesting a dual role for this kinase in tumorigenisis