The major focus of my laboratory is to understand cancer cell biology and to develop innovative anticancer 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. In the long, we hope to translate this knowledge into potential anticancer treatment strategies. Current research 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 of new players or genes with previously unidentified function in DDR, as well as in the DSB repair.
The role of cytoskeletal cues on genome stability
Through a genetic screening, we identified several cytoskeletal proteins that affect the nucleus shape and ultimately genome stability. These studies reveal some previously unidentified insights into how cytoplasmic cues shape the genome integrity in the nucleus. Among them is a non-conventional myosin protein called myosin X. We found that the protein level of myosin X is critical for normal cytoplasm-nucleus crosstalk. We are investigating mechanisms controlling the expression level of myosin X and determine specifically how this gene regulates genome stability and link to aging and cancer.
The genome stability maintenance network functions as a double-edged 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. For instance, our recent discovery opened the door for a new way to treat cancers without the concurrent use of chemotherapeutic drugs. Therefore, this novel concept should significantly reduce the toxic side effect by chemotherapy. We wish to design a better therapy for cancer patients with more effect and less toxicity.
Genome stability, in a simple way, means that the genetic information buried in DNA has to be kept stable. Changes or damages to DNA, if not fixed, often lead to the loss of genome stability. A long-term effect of the loss of genome stability is the occurrence of degenerative diseases, including premature ageing and human cancers. My lab is trying to understand a fundamental biological issue: how the genome stability is maintained in human cells? In detail, we focus on dissecting the molecular signaling networks that maintain the genome stability in human cells.
Virtually every function of the cell is carried out by a number of proteins that form a network within the cell. Genome stability maintenance is no exception. Knowing members of this signaling network is critical for our understanding of how the genome stability is maintained in human cells. We use biochemical, genetic, pharmacological and structural tools to identify proteins involved in this process and characterize their molecular function. In the long, we wish to understand how the genome stability is maintained.
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, in press, 2017. doi: 10.1074/jbc.M116.760645.
Yan Yan, Xiangzi Han, Yulang Qing, Allison G. Condie, Shashank Gority, Shuming Yang, Yan Xu, Youwei Zhang and Stanton Gerson. Inhibition of uracil DNA glycosylase sensitizes cancer cells to 5-fluorodeoxyuridine through replication fork collapse-induced DNA damage. Oncotarget, 7: 59299-59313, 2016, DOI: 10.18632/oncotarget.11151.
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. June 17. doi: 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, published March 25, 2015 as 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, 111, 17456-61, 2014. doi: 10.1073/pnas1408538111. Epub Nov 24, 2014. (# Equal contribution).
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. Jul 21. Pii: jbc.M114.575035.
Youwei Zhang* and Tony Hunter. Roles of Chk1 in cell biology and cancer therapy. International Journal of Cancer (Review), 134, 1013-1023, 2014 (Epub May 28, 2013).
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, Xiujing Feng, Zhenghe Wang, and Youwei Zhang*. Coupling cellular localization and function 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, Callie Merry, 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 the checkpoint kinase Chk1 in cancer therapy. Cell Cycle. 2010 Jan 15;9(2):279-83. Epub 2010 Jan 27.
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, 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.
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, 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, 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, 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.
Ikuo Morita,Youwei Zhang, and Sei-itsu Murota. Eicosapentaenoic acid (EPA) protects endothelial functions injured by hypoxia/reoxygenation. Ann. N. Y. Acad Sci. 947: 394-397, 2001.