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Molecular mechanisms of tumor suppressor functions of HECT-type E3 ligase Smurf2: roles in chromatin organization, dynamics, gene expression and DNA damage response and repair

Final Report Summary - SMURF2 IN CANCER (Molecular mechanisms of tumor suppressor functions of HECT-type E3 ligase Smurf2: roles in chromatin organization, dynamics, gene expression and DNA damage response and repair)

Cancer is the leading cause of morbidity and mortality in the developed world consuming more than eight million human lives each year. Despite significant advances made in the treatment of specific cancer types, eradicating the disease, especially in its most dangerous metastatic forms, has yet to be achieved, emphasizing the urgent need for exploration of novel therapeutic targets and paradigms, and this requires deeper insights of the underlying mechanisms of cancer.
The main objective of our research is to delineate the spectrum of molecular mechanisms operating in the cell under the jurisdiction of Smurf2, an E3 ubiquitin ligase and suggested tumor suppressor gene. Primarily, we focus on the processes operating in and regulating the chromatin organization and dynamics, gene expression, DNA damage repair and genomic integrity maintenance. These fundamentals are essential for normal cellular functions and homeostasis maintenance. In cancer cells, these elements are prominently altered as to provide growth advantage and protection against harsh environment and stresses, including DNA damaging insults produced by anticancer drugs.
During the grant implementation period, we succeeded to meet the majority of the research goals that we set. First, we have established the experimental system required for the analysis, and generated all reagents necessary for this study. Second, we identified previously unknown binding partners/substrates of Smurf2. Among this subset, we focused on molecules with known or presumed involvement in the regulation of our pathways of interest - chromatin organization, dynamics, DNA damage response, gene expression, and genomic integrity maintenance. Third, we confirmed the existence of the interactions between Smurf2 and its selected binding partner/s in different types of mammalian cells. Essentially, we were able to determine the reciprocal relationship between Smurf2 and some of its identified binding partners/substrates in different types of mouse and human normal and cancer cells and tissues. Finally, we succeeded to gain molecular insights into the significance of the interactions between Smurf2 and its binding partners in the biology of the cell.
The execution of this project expanded our knowledge on fundamental biological processes operating in the cell, including protein ubiquitination, genomic integrity regulation, DNA damage response, and chemoresistance. Moreover, our findings provided a missing mechanistic link between chromosomal abnormalities we observed in Smurf2-deficient cells and molecular mechanisms underlying these alterations. Additional knowledge that will be generated by our subsequent studies can provide novel therapeutic targets and cancer treatment paradigm. This paradigm would serve as the intellectual background necessary for the development of new more efficient therapeutic interventions and improved cancer treatment regimens. This knowledge is highly sought by cancer researchers, oncology clinicians, and cancer patients. For these patients, a better therapy is essentially a matter of life or death.
Our next goal is to understand how the interplay between different molecular mechanisms we discovered to operate under Smurf2 auspices affects the ability to tumor cells to grow, disseminate, and withstand anticancer therapies.
Apart of the scientific progress, the integration grant enabled Dr. Blank to establish himself as an independent researcher, and his straightforward integration into the European scientific community. Dr. Blank research programs attracted to his lab promising graduate students and post-doctorate fellows from all around the world; and enabled him to establish collaborations with leading scientists both in his home country and abroad. Moreover, during the grant implementation period Dr. Blank has authored and co-authored several scientific publications. In majority of these publications, Dr. Blank served as a senior author. His additional manuscript is currently under consideration in one of the leading journal in the cell biology field, while three other manuscripts are in preparation. Dr. Blank has also received a few prestigious awards/grants including RCD award from ICRF (USA), and Israel Cancer Association (ICA) grant. The integration grant also enabled Dr. Blank to participate in a few scientific meetings, where he had an opportunity to share his research findings with his peers. In addition, Dr. Blank has organized/co-organized a few scientific meetings, as well as took a part in organizing and conducting European Researchers’ Night at his Faculty, communicating the amazing world of science and its significance to the general public as well.
The detailed information about the research conducted in Dr. Blank’s laboratory can be found at: