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.
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.
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, 7, eabg6908, 2021. doi/10.1126/sciadv.abg6908
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, accepted, 2021.
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, in press, 2021. doi.org/10.1016/j.apsb.2021.08.025
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, 493, 80-90, 2020 (# Equal contribution) 10.1016/j.canlet.2020.08.008
Xinran Geng#, Fangfang Wang#, Danmei Tian, Lihua Huang, Evan Streator, Jingjing Zhu, Hiroshi Kurihara, Rongrong He, Xinsheng Yao, Youwei Zhang* and Jinshan Tang*. Cardiac glycosides inhibit cancer through Na/K-ATPase-dependent cell death induction. Biochemical Pharmacology, 182, 114226, 2020. (# Equal contribution)
Fangfang Wang, Franklin Mayca Pozo, Danmei Tian, Xinran Geng, Xinsheng Yao, Youwei Zhang* and Jinshan Tang*. Shikonin inhibits cancer through P21 upregulation and apoptosis induction. Frontiers in Pharmacology, 11, 861, 2020.
Abbey L Perl, Caitlin M O’Connor, Pengyan Fa, Franklin Mayca Pozo, Junran Zhang, Youwei Zhang and Goutham Narla*. Protein phosphatase 2A controls ongoing DNA replication by binding to and regulating cell division cycle 45 (CDC45). Journal of Biological Chemistry, 294, 17043-17059, 2019.
Fangfang Wang, Xinsheng Yao, Youwei Zhang* and Jinshan Tang*. Synthesis biological function and evaluation of Shikonin in cancer therapy. Fitoterapia, 134, 329-339, 2019.
Jingwen Li, Rong Ding, Hao Gao, Liangdong Guo, Xinsheng Yao, Youwei Zhang* and Jinshan Tang*. New spirobisnaphthalenes from an endolichenic fungus strain CGMCC 3.15192 and their anticancer effects through the P53-P21 pathway. RSC Advances, 9, 39082-39089, 2019.
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, 8, 5713-5730, 2018. (# Equal contribution)
Xiaosan Li, Yichang Ren, Yuzhou Bao, Jie Liu, Xiaokun Zhang, Youwei Zhang, Xuelong Sun, Xinsheng Yao, Jinshan Tang*. Synthesis of C3-neoglycosides of digoxigenin and their anticancer activities. European Journal of Medicinal Chemistry, 145, 252-262, 2018.
Xueping Lei, Minfeng Chen, Maohua Huang, Xiaobo Li, Changzheng Shi, Dong Zhang, Liangping Luo, Youwei Zhang, Nan Ma, Heru Chen, Huafeng Liang, Wencai Ye, and Dongmei Zhang. Desacetylvinblastine monohydrazide disrupts tumor vessels by promoting VE-cadheris internalization. Theranostics, 8:384-398, 2018.
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, 292:5992-6003, 2017.
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, 291:12951-12959, 2016.
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, 290, 12370-12378, 2015.
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, 111, 17456-61, 2014.
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, 289, 24716-24723, 2014.
Youwei Zhang* and Tony Hunter. Roles of Chk1 in cell biology and cancer therapy. International Journal of Cancer, 134, 1013-1023, 2014.
Jingna Wang, Xiangzi Han, and Youwei Zhang*. Auto-regulatory mechanisms of phosphorylation of checkpoint kinase 1 (Chk1). Cancer Research, 72, 3786-3794, 2012.
Jingna Wang, Xiangzi Han, Xiujin Feng, Zhenghe Wang and Youwei Zhang*. Coupling protein phosphorylation and cellular localization of Chk1 in checkpoints and cell viability. Journal of Biological Chemistry, 287, 25501-25509, 2012.
Amitabha Chakrabarti, Kalpana Gupta, Abigail Glick, Youwei Zhang, Munna Agarwal, Mukesh K Agarwal and David N Wald. ATP depletion triggers AML differentiation through an ATR-Chk1 dependent and p53 independent pathway. Journal of Biological Chemistry, 287, 23635-23643, 2012.
John Brognard, Youwei Zhang, Lorena Puto, and Tony Hunter. Cancer-associated loss-of-function mutations implicate DAPK3 as a tumor suppressing kinase. Cancer Research, 71, 3152-3161, 2011.
Jingna Wang, Staci Engle and Youwei Zhang*. A new in vitro system for activating the cell cycle checkpoints. Cell Cycle, 10, 500-506, 2011.
Callie Merry, Jingna Wang, Kang Fu, I-Ju Yeh, and Youwei Zhang*. Targeting Chk1 in cancer therapy. Cell Cycle, 9, 279-283, 2010.
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 Cell, 35, 442-453, 2009.
Zhongsheng You, Linda Z. Shi, Quan Zhu, Peng Wu, Youwei Zhang, Andrew Basilio, Nina Tonnu, Inder Verma, Michael W. Berns, and Tony Hunter. CtIP Links DNA Double-strand Break Sensing to Resection. Molecular Cell, 36, 954-969, 2009.
Youwei Zhang, Tony Hunter, and Robert T. Abraham. Turning the Replication Checkpoint On and Off. Cell Cycle, 5, 125-128, 2006.
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, 19, 607-618, 2005.
Youwei Zhang*, Keiko Nakayama, Kei-Ichi Nakayama, and Ikuo Morita. A Novel Route for Connexin 43 to Inhibit Cell Proliferation: Negative Regulation of Skp2. Cancer Research, 63, 1623-1630, 2003.
Youwei Zhang*, Makoto Kaneda, and Ikuo Morita. A gap junction-independent tumor suppressing effect of connexin 43. Journal of Biological Chemistry, 278, 44852-44856, 2003.
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. Oncogene, 20; 4138-4149, 2001.
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, 180; 305-313, 1999.