Youwei Zhang, PhD

Professor
Department of Pharmacology
School of Medicine
Member
Molecular Oncology Program
Case Comprehensive Cancer Center
Chair
Department of Pharmacology
Graduate Qualification Committee
Vice Chairman
Committee for Biomedical Research
School of Medicine
Co-Leader
Genome Stability and Therapy Program
Case Comprehensive Cancer Center


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.

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

Publications

Fangfang Wang, Meng Zhang, Meng Yuan, Zixuan Xia, Fengge Yang, Sihao Zhang, Tengyu Lin, Lianxiang Luo, Jinshan Tang and Youwei Zhang*. A novel sorbicillinoid compound as a potent anti-inflammation agent through inducing NLRP3 protein degradation. British Journal of Pharmacology, in press 2023. https://doi.org/10.1111/bph.16058

Diana Ainembabazi, Xinran Geng, Navnath S. Gavande, John J. Turchi and Youwei Zhang*. Synthesis and Biological Evaluation of Cardiac Glycosides for Cancer Therapy by Targeting the DNA Damage Response. ChemMedChem, 2022, e20220041. 10.1002/cmdc.202200415.
 
Fangfang Wang, Sora Jin, Franklin Mayca Pozo, Danmei Tian, Xiyang Tang, Yi Dai, Xinsheng Yao, Jinshan Tang and Youwei Zhang*. Chemical screen identifies Shikonin as a broad DNA damage response inhibitor that sensitizes chemotherapy through inhibiting ATM and ATR. Acta Pharmaceutica Sinica B, 2022, 12, 1339-1350. doi.org/10.1016/j.apsb.2021.08.025
 
Lei Zhang, Xinran Geng, Fangfang Wang, Jinshan Tang, Yu Ichida, Sharma Arishya, Sora Jin, Minyue Chen, Mingliang Tang, Franklin Mayca Pozo, Wenxiu Wang, Janet Wang, Michal Wozniak, Xiaoxia Guo, Masaru Miyagi, Fulai Jin, Yongjie Xu, Xinsheng Yao and Youwei Zhang*. 53BP1 regulates heterochromatin through liquid phase separation. Nature Communications, 2022, 13, 360. 10.1038/s41467-022-28019-y.
 
Raul Jobava, Yuanhui Mao, Bo-Jhih Guan, Dawid Krokowski, Erica Shu, Di Hu, Evelyn Chukwurah, Jing Wu, Zhaofeng Gao, Leah L. Zagore, William C. Merrick, Youwei Zhang, Xin Qi, Eckhard Jankowsky, Ivan Topisirovic, Donny D. Licatalosi, Shu-Bing Qian and Maria Hatzoglou.Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress. Molecular Cell, 2021, 81, 4191-4208.
 
Franklin Mayca Pozo, Xinran Geng, Ilaria Tamagno, Mark Jackson, Ernest G. Heimsath, John Hammer, Richard Cheney and Youwei Zhang*. MYO10 drives genomic instability and inflammation in cancer. Science Advances, 2021, 7, eabg6908. doi: 10.1126/sciadv.abg6908
 
Danmei Tian, Jinshan Tang, Xinran Geng, Qingwen Li, Fangfang Wang, Huadong Zhao, Goutham Narla, Xinsheng Yao and Youwei Zhang*. Targeting UHRF1-dependent DNA repair selectively sensitizes KRAS mutant lung cancer to chemotherapy. Cancer Letters, 2020, 493, 80-90. DOI: 10.1016/j.canlet.2020.08.008
 
Yifang Li, Shuhua Ouyang, Longfang Tu, Xi Wang, Weilin Yuan, Guoen Wang, Yanping Wu, Wenjun Duan, Hongmin Yu, Zhongze Fang, Hiroshi Kurihara, Youwei Zhang* and Rongrong He*. Caffeine protects skin from oxidative stress-induced senescence through the activation of autophagy. Theranostics, 2018, 8, 5713-5730.
 
 
Franklin Mayca Pozo, Jinshan Tang, Kristine W Bonk, Ruth A Keri, Xinsheng Yao and Youwei Zhang*. Regulatory crosstalk determines the cellular levels of 53BP1, a critical factor in DNA repair. Journal of Biological Chemistry, 2017, 292, 5992-6003. DOI: 10.1074/jbc.M116.760645
 
Xiangzi Han, Jinshan Tang, Jingna Wang, Jinhua Zheng, Feng Ren, Megan Gragg, Philip Kiser, Paul Park, Krzysztof Palczewski, Xinsheng Yao and Youwei Zhang*. Conformational change of human checkpoint kinase 1 (Chk1) induced by DNA damage. Journal of Biological Chemistry,2016, 291, 12951-12959. https://doi.org/10.1074/jbc.M115.713248
 
Xiangzi Han, Franklin Mayca Pozo, Jacob N Wisotsky, Benlian Wang, James Jacobberger, and Youwei Zhang*. Phosphorylation of mini-chromosome maintenance 3 (MCM3) by Chk1 negatively regulates DNA replication and checkpoint activation. Journal of Biological Chemistry,2015, 290, 12370-12378. DOI: 10.1074/jbc.M114.621532
 
Xiangzi Han, Lei Zhang, Jin Sil Chung, Franklin Mayca Pozo, Amada Tran, Darcie Searchist, James Jacobberger, Ruth Keri, Hannah Gilmore and Youwei Zhang*. UbcH7 regulates 53BP1 stability and DSB repair. Proceedings of the National Academy of Sciences, 2014, 111, 17456-61. DOI: 10.1073/pnas.1408538111
 
Xiangzi Han, Aaron Aslania, Kang Fu, Toshiya Tsuji, and Youwei Zhang*. The interaction between Chk1 and the MCM complex is required for DNA damage induced Chk1 phosphorylation. Journal of Biological Chemistry, 2014, 289, 24716-24723. DOI: 10.1074/jbc.M114.575035
 
Youwei Zhang* and Tony Hunter.  Roles of Chk1 in cell biology and cancer therapy. International Journal of Cancer (Review), 2014, 134, 1013-1023. DOI: 10.1002/ijc.28226
 
Jingna Wang, Xiangzi Han, Xiujin Feng, Zhenghe Wang and Youwei Zhang*. Coupling cellular localization and function of Chk1 in checkpoints and cell viability. Journal of Biological Chemistry, 2012, 287, 25501-25509. DOI: 10.1074/jbc.M112.350397
 
Jingna Wang, Xiangzi Han, and Youwei Zhang*. Autoregulatory mechanisms of phosphorylation of checkpoint kinase 1. Cancer Research2012, 72, 3786-3794. DOI: 10.1158/0008-5472.CAN-12-0523
 
Jingna Wang, Staci Engle and Youwei Zhang*. A new in vitro system for activating the cell cycle checkpoints.  Cell Cycle, 2011, 10, 500-506. DOI: 10.4161/cc.10.3.14753
 
Youwei Zhang*, John Brognard, Chris Coughlin, Zhongshen You, Marisa Dolled-Filhard, Aaron Aslanian, Gerard Manning, Robert T.  Abraham, and Tony Hunter. The F-box protein Fbx6 regulate Chk1 stability and cellular sensitivity to replication stress.  Molecular Cell2009, 35, 442-453. DOI: 10.1016/j.molcel.2009.06.030
 
Youwei Zhang, Dianne M. Otterness, Gary G. Chiang, Yuncai Liu, Weilin Xie, Frank Mercurio, and Robert T. Abraham. Genotoxic Stress Targets Human Chk1 for Degradation by the Ubiquitin-Proteasome Pathway.  Molecular Cell, 2005, 19, 607-618. DOI: 10.1016/j.molcel.2005.07.019
 
Youwei Zhang*, Makoto Kaneda, and Ikuo Morita. The gap junction-independent tumor suppressing effect of connexin 43.  Journal of Biological Chemistry, 2003, 278, 44852-44856. DOI: 10.1074/jbc.M305072200
 
Youwei Zhang*, Keiko Nakayama, Kei-Ichi Nakayama, and Ikuo Morita. A Novel Route for Connexin 43 to Inhibit Cell Proliferation: Negative Regulation of S-phase kinase-associated protein (Skp2).  Cancer Research, 2003, 63, 1623-1630.
 
Youwei Zhang, Ikuo Morita, Masa-aki Ikeda, Kai-Wen Ma, and Sei-itsu Murota. Connexin 43 suppresses proliferation of osteosarcoma U2OS cells through posttranscriptional regulation of p27.  Oncogene2001, 20: 4138-4149. DOI: 10.1038/sj.onc.1204563
 
Youwei Zhang, Ikuo Morita, Masamichi Nishida, and Sei-itsu Murota. Involvement of tyrosine kinase in the hypoxia/reoxygenation-induced gap junctional intercellular communication abnormality in cultured human umbilical vein endothelial cells.  Journal of Cellular Physiology, 1999, 180, 305-313. 
 
 
*Selected publications listed, please check back for a link to further publications.