Zhongsheng You, PhD


Zhongsheng You PhotoI am a Professor in the Department of Cell Biology and Physiology at Washington University School of Medicine. I received my college education at Zhejiang University from 1990-1994, a period during which I published my first paper in a scientific journal. This experience was pivotal in cementing my aspiration for a career in research and education. After receiving a Master’s degree from the Shanghai Institute of Biochemistry at the Chinese Academy of Sciences in 1997, I pursued my PhD study in the University of California San Diego under the mentorship of Dr. John Newport. My research there revealed novel mechanisms of cell cycle regulation by protein degradation and checkpoint pathways. For my postdoctoral training, I joined Dr. Tony Hunter’s lab at Salk Institute in 2002, where I studied how the cell senses and signals the presence of DNA double-strand break (DSB) damage to promote proper DNA repair. My work in the Hunter Lab led to the discovery that ATM, a master kinase that governs the DSB damage response, is activated directly at DNA lesions after damage and that the DNA regions flanking DSBs are important for the optimal activation of ATM. Furthermore, I found that the Nijmegen breakage syndrome protein NBS1 is a functional partner that directly interacts with and activates ATM in response to DNA damage. In 2009, I established my own lab at Washington University in St. Louis to study both DNA and RNA surveillance and their cancer relevance. In addition to laboratory research, I have been actively involved in teaching and student training and have served as a Co-Director of the Molecular Cell Biology Graduate Program since 2019.


My lab studies DNA and RNA surveillance mechanisms in human cells and the potential of targeting these mechanisms for cancer treatment. Our current work in DNA surveillance focuses on a newly identified, cytosolic DNA/Ca2+-dependent signaling pathway that functions to protect the genome during replication stress. We are also exploring the roles of this pathway in other cellular processes, including innate immunity, autophagy and senescence. In the RNA surveillance area, we focus on the nonsense-mediated RNA decay (NMD) pathway, which eliminates aberrant transcripts with premature translation termination codons as well as certain physiological transcripts. Our latest findings suggest that blocking NMD inhibition could be an effective treatment strategy for hematological malignancies with mutations in spliceosome factor genes. This sensitivity to NMD inhibition is primarily caused by aberrant accumulation of R loops in the genome and defects in DNA replication. Our ongoing work aims to further test the therapeutic potential of NMD inhibition in cancer using animal models and to elucidate the connections between NMD, R loops and genome maintenance.

Youlab Merged (002)

Lab website: http://youlab.wustl.edu

Selected publications

    1. Li S, Kong L, Meng Y, Cheng C, Lemacon DS, Yang Z, Tan K, Cheruiyot A, Lu Z and You Z. Cytosolic DNA Sensing by cGAS/STING Promotes TRPV2-Mediated Ca2+ Release to Protect Stressed Replication Forks.  Molecular Cell 2023, 83:556-573.
    2. 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. Ca2+-stimulated AMPK-dependent Phosphorylation of Exo1 Protects Stressed Replication Forks from Aberrant Resection. Molecular Cell 2019; 74: 1123-1137.
    3. Cheruiyot A*, Li S*, Nonavinkere SS, Ahmed T, Chen Y, Lemacon DS, Li Y, Tang Z, Wadugu BA, Warner WA, Pruett-Miller SM, Obeng EA, Lin DC, He D, Xiao F, Bailis JM, Walter MJ, You Z. Nonsense-mediated RNA Decay Is a Unique Vulnerability of Cancer Cells Harboring SF3B1 or U2AF1 Mutations. Cancer Research 2021; 18:4499-4513
    4. Nickless A, Jackson E, Marasa J, Nugent P, Mercer RW, Piwnica-Worms D* and You Z* (2014). Intracellular Calcium Regulates Nonsense-mediated mRNA Decay. Nature Medicine 20: 961-966.
    5. You Z, Shi L, Zhu Q, Zhang Y, Basilio A, Tonnu N, Verma I, Berns M and Hunter T.  CtIP Links DNA Double-strand Break Sensing and Resection. Molecular Cell 2009; 36(6): 954-969.