For years, researchers have known that our genome is protected by a system of detection, evaluation and repair processes that activate any time DNA damage occurs. Upon detection, the damage is assessed, repaired in one way or another, or, if it can’t be repaired the cell is cued to self-destruct. Much of that effort is set in motion by a signaling process involving the protein ubiquitin. Enzymes called ubiquitin ligases are charged with the task of tagging the damaged DNA with this ubiquitin protein to call in more help. What hasn’t been clear is how two of the key enzymes that mark the sites of DNA damage and amplify the repair response are called to action. Researchers theorized there was another actor involved, a missing link. Now Mayo Clinic researchers have discovered that link.
It’s L3MBTL2 – which stands for lethal-3 malignant brain tumor-like protein 2. It orchestrates the ubiquitin signaling resulting in the recruitment of the enzymes called RNF8 and RNF168 in a specific sequence. The Mayo findings were published in Nature Cell Biology.
“To our knowledge, this is the first known report tying L3MBTL2 to DNA damage control,” says Zhenkun Lou, Ph.D., Mayo Clinic oncology researcher and senior author of the article. “Our finding also challenges the currently accepted theory that a histone, H1, is the primary link in this process.”
Significance of findings
Efficient repair of DNA strand breaks is the frontline in preventing mutations that could turn into cancer. Anything that interrupts that process or impedes programmed cell death could result in more damage or tumor development. The researchers emphasize that it’s important that this repair process be thoroughly understood in order to develop effective therapies to treat or prevent cancer. They further state that mutations in L3MBTL2 – when found in cancer patients – may damage or hinder the DNA repair process.
The research was supported by grants from the National Institutes of Health, including the National Cancer Institute, which funds the Mayo Clinic Cancer Center, and also by the Laura J. Siegel Breast Cancer Fellowship Award from the Foundation for Women’s Wellness.
In addition to Mayo Clinic scientists, the study included collaboration and coauthors from Jinan University, Guangzhou, China; The University of Minnesota Hormel Institute, Austin, Minnesota; and Tongji University School of Medicine, Shanghai, China.