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DNA damage induces nuclear envelope rupture through ATR-mediated phosphorylation of lamin A/C. | LitMetric

AI Article Synopsis

  • * The study indicates that DNA damage activates the ATR pathway, causing phosphorylation of lamin A/C, which disrupts the lamina structure and leads to NE rupture.
  • * Cancer cells with inherent DNA repair issues frequently experience NE rupture due to DNA damage, suggesting that targeting this vulnerability could enhance the efficacy of existing chemotherapy treatments.

Article Abstract

The integrity of the nuclear envelope (NE) is essential for maintaining the structural stability of the nucleus. Rupture of the NE has been frequently observed in cancer cells, especially in the context of mechanical challenges, such as physical confinement and migration. However, spontaneous NE rupture events, without any obvious physical challenges to the cell, have also been described. The molecular mechanism(s) of these spontaneous NE rupture events remain to be explored. Here, we show that DNA damage and subsequent ATR activation leads to NE rupture. Upon DNA damage, lamin A/C is phosphorylated in an ATR-dependent manner, leading to changes in lamina assembly and, ultimately, NE rupture. In addition, we show that cancer cells with intrinsic DNA repair defects undergo frequent events of DNA-damage-induced NE rupture, which renders them extremely sensitive to further NE perturbations. Exploiting this NE vulnerability could provide a new angle to complement traditional, DNA-damage-based chemotherapy.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10597398PMC
http://dx.doi.org/10.1016/j.molcel.2023.09.023DOI Listing

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