Zhongsheng You, Ph.D.

Associate Professor
Cell Biology and Physiology
Internal Medicine

Molecular Cell Biology Program
Molecular Genetics and Genomics Program
Biochemistry, Biophysics, and Structural Biology Program
Biomedical Informatics and Data Science Program

  • 314-362-9893

  • 314-362-4668

  • 314-422-5223 (cell)

  • 314-362-7463

  • 8228

  • McDonnell Sciences Building, Room 514

  • zyou@wustl.edu

  • http://youlab.wustl.edu

  • cancer, DNA damage response, RNA surveillance, cell cycle, chromatin, laser micro-irradiation, Xenopus egg extracts, imaging, genetically-encoded reporters

  • DNA and RNA surveillance systems and their relation to cancer formation and treatment

Research Abstract:

The surveillance systems that safeguard the genome and the transcriptome ensure faithful transmission and expression of genetic information and determine the function and the fate of the cell. Defects in these systems are associated with cancer, aging and neurological disorders. Our laboratory is interested in understanding the molecular basis of the DNA and RNA surveillance systems and their relation to human diseases, especially cancer.

Our work in DNA surveillance is focused on the cellular response to the most dangerous type of DNA damage, DNA double-strand breaks. This highly sophisticated DNA damage response suppresses cancer formation and is also an important target of cancer therapy. Our work has contributed to the understanding of a number of key biochemical processes such as ATM activation and DNA end resection in the DNA damage response. Currently, we are pursuing the following fundamental questions: 1. How do cells read the DNA damage signal and translate the signal into downstream checkpoint and repair responses? 2. How do cells maintain genome stability during DNA replication and gene expression?

In the RNA surveillance area, we focus on the nonsense-mediated mRNA decay (NMD) pathway. NMD selectively eliminates aberrant transcripts harboring premature translation termination codons and also regulates the levels of many physiological mRNAs. NMD is an attractive target of therapeutic intervention for cancer and other genetic diseases (e.g., cystic fibrosis and Duchenne muscular dystrophy). Through a high-throughput drug screen using a novel reporter system, we have recently identified a group of cardiac glycosides such as ouabain and digoxin as potent inhibitors of NMD. Furthermore, we have discovered that intracellular calcium is a key regulator of NMD. Our current work is aimed at elucidating the mechanism and physiological significance of the calcium regulation of NMD. In addition, we are pursuing the potential connections between RNA surveillance and DNA surveillance pathways.

We employ a powerful combination of experimental systems and tools, including human cell culture, Xenopus egg extracts, laser microirradiation, genetically encoded reporters and live cell imaging, to dissect the DNA and RNA surveillance systems—with the long-term goal of improving the treatment of cancer and other diseases.

Selected Publications:

Li S, Lavagnino Z, Lemacon D, Kong L, Ustione A, Ng X, Zhang Y, Wang Y, Zheng B, Piwnica-Worms H, Vindigni A, Piston DW and You Z (2019). Ca2+-stimulated AMPK-dependent Phosphorylation of Exo1 Protects Stressed Replication Forks from Aberrant Resection. Molecular Cell, doi: 10.1016

Cheruiyot A*, Li S*, Nickless A, Roth R, Fitzpatrick JAJ and You Z (2018). Compound C Inhibits Nonsense-mediated RNA Decay Independently of AMPK. PLoS One 13:e0204978.

Paudyal SC, Li S, Yan H, Hunter T and You Z (2017). Dna2 Initiates Resection at Clean DNA Double-strand Breaks. Nucleic Acids Research 45(20): 11766-11781.

Nickless A, Cheruiyot A, Flanagan K, Piwnica-Worms, D, Stewart S and You Z (2017). p38 MAPK Inhibits Nonsense-mediated RNA Decay in Response to Persistent DNA Damage in Non-cycling Cells. Journal of Biological Chemistry, 292: 15266-15276.

Cheruiyot A*, Paudyal SC*, Kim IK*, Sparks M, Ellenberger T, Piwnica-Worms H, and You Z. (2015) Poly(ADP-ribose)-binding Promotes Exo1 Damage Recruitment and Suppresses Its Nuclease Activity. DNA Repair 35: 106-115.

Chen X, Kim IK, Honaker Y, Paudyal SC, Koh WK, Sparks M, Li S, Piwnica-Worms H, Ellenberger T and You Z (2015). 14-3-3 Proteins Restrain the Exo1 Nuclease to Prevent Over-resection. Journal of Biological Chemistry 290: 12300-12.

Nickless A, Jackson E, Marasa J, Mercer RW, Piwnica-Worms D*, You Z* (2014). Intracellular calcium regulates nonsense-mediated mRNA decay. Nature Medicine 20(8): 961-966.

Chen X, Paudyal SC, Chin RI, You Z (2013). PCNA promotes processive DNA end resection by Exo1. Nucleic Acids Research 41(20): 9325-38

You Z*, Shi L, Zhu Q, Wu P, Zhang Y, Basilio A, Tonnu N, Verma I, Berns M and Hunter T* (2009). CtIP Links DNA Double-strand Break Sensing to Resection. Molecular Cell 36:954-969.

You Z, Bailis J, Johnson S, Dilworth S and Hunter T (2007). Rapid Activation of ATM on DNA Flanking Double-Strand Breaks, Nature Cell Biology 9:1311-1318.

Last Updated: 5/1/2019 10:51:14 AM

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