Youwei Zhang obtained his Ph.D. degree from Tokyo Medical & Medical University in Tokyo, Japan in 2002, and trained as a postdoctoral fellow with Dr. Bob Abraham at The Burnham Institute (2002-2005) and then a Senior Research Associate with Dr. Tony Hunter at The Salk Institute (2006-2009) on cancer biology and molecular signaling. Since becoming independent as a tenure track Assistant Professor in April 2009 at CWRU, he has developed a well-funded, internationally recognized research program in genome stability and cancer with publications in prestigious journals including Molecular Cell, Science Advances, Nature Communications, PNAS, Cancer Research, Acta Pharmaceutica Sinica B (2021 IF 14.9), Theranostics (2021 IF 11.5), JBC, Cancer Letters, etc. Youwei was promoted to Associate Professor with tenure in 2016. He has served as ad hoc grant reviewers nationally (ACS, NIH, and DoD) and internationally. He organized a national meeting on DNA damage repair in 2018 at CWRU, served as session chairs on several national meetings, and was invited to give talks in international conferences. He has trained more than 50 students and postdoc fellows, and several of them have become faculty members at universities (like Peking University) or Senior personnel in industrial companies. His lab has been continuously supported by external funding including NIH/NCI and American Cancer Society.
My research focuses on molecular mechanisms regulating genome stability and their potential application in cancer therapy.
Research Information
Research Interests
The major focus of my laboratory is to understand cell biology and cancer etiology with a ultimate goal of developing innovative anti-cancer therapies. I have long been interested in understanding a fundamental biology question, that is ‘how our cells protect the integrity of the DNA?’ This is critical, because failure to do so will cause genome instability and eventually leads to the early onset of degenerative human disorders such as premature aging and cancer. Our goal is to understand the molecular mechanisms that maintain the genome stability in human cells by identifying the genes and the signaling pathways involved. We use biochemical, genetic, pharmacological and structural tools to identify proteins involved in this process and characterize their molecular function. In the long, we hope to translate this knowledge into potential anti-cancer treatment strategies. Current research in the lab focuses on the following directions.
Mechanisms underlying the DNA damage response and DSB repair
In response to DNA damage, such as DNA double-strand break (DSB), cells will mount an evolutionally conserved signaling pathway, called the DNA damage response (DDR), to sense the presence and initiate the repair of DNA damage. This is critical for the maintenance of genome stability and functions as a barrier against tumorigenesis. We are interested in identifying and characterizing the function new players or genes with previously unidentified function in DDR, as well as in the DSB repair.
Involvement of liquid-liquid phase separation at heterochromatin
Liquid-liquid phase separation (or LLPS in short) is emerging as a forefront of biological research, especially in cellular activities that involve the assembly of multiple macromolecules consisting of proteins and/or nucleotides. LLPS has been reported to regulate protein translation, gene transcription, cellular structure organization, etc. Our recent findings revealed a previously uncharacterized aspect of heterochromatin through a DSB repair protein, 53BP1. Importantly, we demonstrated that this novel function of 53BP1 is independent of its canonical role in DSB repair, but involves its LLPS with the heterochromatin protein HP1a. These studies open a new research direction for both 53BP1 and heterochromatin.
The role of cytoskeletal cues on genome stability
Through a genetic screening, we identified a non-conventional myosin protein called MYO10 that regulates the nucleus shape through which it mediates genome stability. These studies reveal some previously unidentified insights into how cytoplasmic cues shape the genome integrity in the nucleus. We found that the protein level of MYO10 is critical for the normal cytoplasm-nucleus crosstalk. We further demonstrated that MYO10 regulates inflammation and promote tumor growth. Yet, the pro-inflammatory tumor environment created by MYO10 high expression favored the therapy response of immune checkpoint blockades. These studies reveal an unprecedented insight into genome stability regulation and cancer therapy.
Anticancer therapy
The genome stability maintenance network functions as a double-edge sword. At one hand, it protects the cell's DNA from damage. On the other hand, it has remained a central target in cancer therapy. The idea underpinning this strategy is that inhibiting the genome stability maintenance network makes cancer cells extremely sensitive to agents that damage their DNA, inducing the cell killing effect. Our laboratory is also interested in translate the knowledge that we gained above from bench to bed. The long-term goal is to cure or control cancers to increase the quality of life. Studies done in my lab have the potential to be translated into potential treatment for human diseases, including cancers. We have been collaborating with chemists to design better and safer chemicals that will show potential in combating human diseases, particularly cancer.
For more information on lab members, please visit the lab website