Researchers at the University of Toronto have discovered a DNA repair mechanism that advances understanding of how human cells stay healthy, and which could lead to new treatments for cancer and premature aging. The research solves the mystery of how DNA double-strand breaks and the nuclear envelope connect for repair in human cells. It also makes many previously published discoveries in other organisms applicable in the context of human DNA repair, which should help science move even faster.

 

DNA double-strand breaks arise when cells are exposed to radiation and chemicals, and through internal processes such as DNA replication. They are one of the most serious types of DNA damage. In 2015, Mekhail and collaborators showed how motor proteins deep inside the nucleus of yeast cells transport double-strand breaks to 'DNA hospital-like' protein complexes embedded in the nuclear envelope at the edge of the nucleus. Other studies uncovered related mechanisms during DNA repair in flies and other organisms. When DNA inside the nucleus of a human cell is damaged, a specific network of microtubule filaments forms in the cytoplasm around the nucleus and pushes on the nuclear envelope. This prompts the formation of tiny tubes, or tubules, which reach into the nucleus and catch most double-strand breaks. Enzymes called DNA damage response kinases and tubulin acetyltransferase are the master regulators of the process, and promote the formation of the tubules. Enzymes deposit a chemical mark on a specific part of the microtubule filaments, which causes them to recruit tiny motor proteins and push on the nuclear envelope. Consequently, the repair-promoting protein complexes push the envelope deep into the nucleus, creating bridges to the DNA breaks.

 

The findings have significant implications for some cancer treatments. Normal cells use the nuclear envelope tubules to repair DNA, but cancer cells appear to need them more. "Until now, scientists were unclear as to the relative impact of the nuclear envelope in the repair of damaged DNA in human cells. Our collaboration revealed that targeting factors that modulate the nuclear envelope for damaged DNA repair effectively restrains breast cancer development," Hakem says. The findings suggest that in progeria, DNA repair may be compromised by the presence of too many or poorly regulated tubules. The study results also have implications for many other clinical conditions, Mekhail says.