Eukaryotic cells have evolved an elaborate network of genome surveillance and repair
proteins to insure that DNA replication occurs in an accurate and timely fashion.
This surveillance pathway is termed the S-phase replication checkpoint. The replication
checkpoint monitors the progress of replication forks, and when the fork stalls,
transmits signals that delay S-phase progression, and maintain the stability of
stalled forks so that DNA replication can resume after the initial error is corrected.
Two key components of the replication checkpoint are the apical protein kinase,
ATR, and its downstream target kinase, Chk1. Replicative stress induces activation
of ATR, which then induces activation of Chk1 through phosphorylating it at Ser317
and Ser345. Activated Chk1 will activate a cascade of downstream effectors, which
will eventually induce cell cycle arrest and damage repair to maintain cell survival,
or cell death if the damage is too severe to be repaired.
My laboratory is interested in dissecting the detailed molecular mechanisms underlying
the activation of the replication checkpoint, and translating that knowledge into
potential anticancer treatment.
Selected Publications:
John Brognard, You-Wei 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 You-Wei Zhang. A new in vitro system for activating the cell cycle checkpoint. Cell Cycle, 10, 500-506, 2011.
Callie Merry, Jingna Wang, Kang Fu, I-Ju Yeh, and You-Wei Zhang
. Targeting Chk1 in cancer therapy. Cell Cycle, 9, 1-5, 2010.
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.
You-Wei 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.
You-Wei Zhang, Tony Hunter, and Robert T. Abraham. Turning the
Replication Checkpoint On and Off. Cell Cycle, 5, 125-128, 2006.
You-Wei 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.
You-Wei Zhang, Makoto Kaneda, and Ikuo Morita. A gap junction-independent
tumor suppressing effect of connexin 43. Journal of Biological Chemistry
278, 44852-44856, 2003.
You-Wei 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.
You-Wei 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.
You-Wei 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, You-Wei Zhang, and Sei-itsu Murota. Eicosapentaenoic
acid (EPA) protects endothelial functions injured by hypoxia/reoxygenation. Ann.
N. Y. Acad Sci. 947: 394-397, 2001.