Project 451893

Our human body comprises trillions of cells whose DNA is packaged inside a balloon-like nuclear envelope and can be damaged by various factors such as smoking and unsafe exposure to the sun. Therefore, the survival and health of our cells depend on processes that recognize and repair damaged DNA. Notably, the human nuclear envelope somehow ensures the repair of damaged DNA, even if most of the damaged DNA appears far from the nucleus's edge. So, how the envelope promotes human DNA repair remains a mystery. Here we pursue new findings suggesting that in cells with damaged DNA, rod-like structures called microtubules poke the exterior of the balloon-like nuclear envelope at multiple points, creating a network of finger-like nuclear envelope invaginations. These finger-like invaginations may contact damaged DNA and drive its repair by sticking the broken DNA ends to each other. The invaginations are omnipresent in breast cancer cells suggesting an increased reliance on these finger-like structures to repair accumulating DNA damage. We have two main objectives. First, we will decipher how the remodeled nuclear envelope mediates DNA repair to ensure cell survival. Second, we will study whether the increased reliance of breast cancer cells on these invaginations for DNA repair and cell survival can be exploited to fight cancer. Overall, this work will uncover critical health-related knowledge about DNA repair, cell survival, and growth while revealing how it can be applied to combat deadly human diseases.