ATR is a protein kinase that controls DNA damage response (DDR), together with ATM, Chk1 and Chk2. DDR genes are often mutated in cancer cells and act as an anti-cancer barrier in response to oncogenic stimuli. ATR is essential and protects the integrity of replicating chromosomes, prevents fragile site expression and aberrant condensation events. While the tumour suppressive role of ATR in mediating the DNA damage response has been extensively studied, the recent findings from the Foiani’s laboratory that ATR controls chromatin association to the nuclear envelope and responds to mechanical stress by re-localizing at nuclear membranes, prompted us to propose a novel role for ATR in controlling cellular and nuclear plasticity.
Using multidisciplinary techniques and experimental approaches, including AFM, micropattern and innovated cell stretching and cell compression device, we quantitatively studied how ATR acts on cellular and nuclear plasticity. We found that ATR functions control cell plasticity, which sense mechanical stress. Basically, ATR-defective cells become twice softer than normal cells. At spatio-temporal level, the mechano-response occurs primarily through the actin cytoskeleton, which forms the cellular mechanical system linking the extracellular microenvironment to the nucleus. We investigated the connection between ATR and actin and we surprisingly found out that ATR directly controls nuclear plasticity, which in turn controls cell plasticity, rather than play a role in actin organization and dynamics. ATR defective cells have compromised nuclear morphology and organization; these cells are highly susceptive to mechanical stress, and have a lower survive rate during interstitial migration. These results suggest that ATR could play an active role in influencing the metastatic process, thus implying that ATR may possess a tumorigenic function.
This line of research contributes to open new directions in the ATR field and to link the control of cellular and nuclear plasticity with the capability of cells in interstitial migration. Thus it might lead to novel target for cancer metastasis and new cancer drug discovery.
