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Gene integrity is continuously challenged by DNA lesions caused by normal metabolic activities or environmental factors. In the event of a DNA break, the cell activates DNA damage response pathways that allow detection and repair of the lesion. Failures to repair are important sources of genome instability, giving rise to chromosomal aberrations and severe biological consequences including tumorigenesis and cell death. Although studies have been conducted to explore changes in the physical organization of the nucleus in response to DNA damage, the description remains incomplete mainly due to the limitation of the existing technologies. However, research has shown that both DNA damage and repair lead to the activation of different biochemical pathways and to major nuclear reorganization, for which alteration of the nucleus mechanics has been increasingly recognized as the hallmark event. Direct measurement of the mechanical behavior of the interior of the nucleus is thus expected to give a better understanding of the structural changes that accompany the cell response to DNA damage.