Researchers have uncovered a new molecular mechanism whereby human cells protect their genome from the detrimental effect of UV radiation and govern DNA replication in cellular mitosis, which, when it malfunctions, leads to harmful results.
The study, from the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University in Philadelphia, investigated the function of NONO, a multifunctional cellular protein, in the cellular response to UV radiation and its role in the growth of cancerous tumors and lesions. UV radiation causes harmful DNA lesions and carcinogenesis, representing the main risk factor for skin cancers and melanoma.
The study appeared last month in the advanced online publication of Oncogene, a leading journal in cancer research from the Nature Publishing Group.
Normally, cells respond to radiation-induced DNA damage by activating different 'checkpoints' which stall the cell cycle and activate DNA repair pathways, preventing the damaged DNA from erroneously replicating in the S (DNA synthesis) phase, or transmitting to daughter cells during mitosis. When the function of the NONO protein is silenced, the cell's 'checkpoint' response is impaired. NONO-silenced cells, compared with control cells, fail to activate cell cycle checkpoints, continue to synthesize DNA, and fail to activate the biochemical cascade of events ultimately leading to DNA repair. Further supporting the finding that NONO is involved in this cellular response, the authors found that, in healthy cells, NONO localizes at the sites of DNA damage where it enables the actions of other proteins which are key to the DNA repair process.
"Our study provides an important missing link which contributes to further dissecting the complex cascade of events that orchestrate the cellular response to DNA damage," says Luigi Alfano, PhD of the National Cancer Institute of Naples- Pascale Foundation - CROM- Cancer Research Center of Mercogliano, Italy and lead author of the study.
"Considering that many studies are identifying NONO alterations in cancer, our findings will likely help to shed light on the molecular mechanisms of tumorigenesis, especially in tumor types like melanoma, in which exposure to UV radiation plays such a prominent part. Our work also provides the preclinical framework supporting the development of new agents targeting NONO that could be used to sensitize cancer cells to a variety of drugs that cause DNA damage, such as common chemotherapy agents," states Francesca Pentimalli PhD from the National Cancer Institute of Naples, who co-authored the study with Antonio Giordano, MD, PhD, Director and Founder of the of the Sbarro Institute for Cancer Research and Molecular Medicine, at Temple University, Philadelphia.
Sbarro Health Research Organization