Researchers from the lab of Antonio Giordano, MD, PhD, Director and Founder of the Sbarro Institute for Cancer Research and Molecular Medicine at Temple University in Philadelphia, PA, have uncovered a new molecular mechanism whereby human cells protect their genome from the detrimental effect of UV radiations. UV radiations by directly causing harmful DNA lesions contribute to carcinogenesis and represent the main risk factor for skin cancer, including melanoma.
The study appeared as advanced online publication on Oncogene, a journal in cancer research from the Nature Publishing Group. Here, the authors investigated the function of NONO, a multifunctional protein involved in melanoma development and progression, in the cellular response to UV radiations.
Normally, cells respond to radiation-induced DNA damage by activating different ‘checkpoints’ which allow to stall cell cycle and activate DNA repair pathways avoiding that damaged DNA is erroneously replicated in the S (DNA synthesis) phase or transmitted to daughter cells during mitosis. 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, showed that silencing NONO impairs cancer cell response following exposure to UV radiations. NONO-silenced cells, compared with control cells, fail to activate cell cycle checkpoints, continue to synthesize DNA and do not efficiently activate the biochemical cascade of events that ultimately lead to DNA repair. Further supporting the finding that NONO is involved in this cellular response, the authors found that NONO localizes at the sites of DNA damage where it favours the loading of other proteins which are key to this 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 Alfano.
“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 tumour types like melanoma, in which exposure to UV radiations 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 co-corresponding of the study with Antonio Giordano, Director of the Sbarro Institute for Cancer Research and Molecular Medicine, at Temple University, Philadelphia.
- L Alfano, C Costa, A Caporaso, A Altieri, P Indovina, M Macaluso, A Giordano, F Pentimalli. NONO regulates the intra-S-phase checkpoint in response to UV radiation. Oncogene, 2015; DOI: 10.1038/onc.2015.107