Zhongsheng You, PhD

Bio

Zhongsheng You PhotoI am an Associate Professor 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 solidified my interest in pursuing a career in research and education. After obtaining an MS from the Shanghai Institute of Biochemistry, Chinese Academy of Sciences, in 1997, I came as a graduate student to the University of California San Diego, where I trained with Dr. John Newport. My research in the Newport Lab focused on cell cycle regulation by protein degradation and checkpoint signaling. 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 at DNA lesions 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 joined the Department of Cell Biology and Physiology at Washington University in St. Louis as an assistant professor. In addition to lab 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.

Research

My lab studies the molecular mechanisms of genome maintenance in human cells. Our research aims to decipher the cellular responses to DNA double-strand break (DSB) damage and replication stress, defects of which are known to promote cancer formation. A major focus of our current work is to further dissect this novel signaling pathway, in particular, the ion channel(s) and signal transducers responsible for Ca2+ induction after replication stress for genome protection. We are also interested in how defects in RNA surveillance affect genome stability, focusing on nonsense-mediated RNA decay (NMD), a pathway that eliminates aberrant transcripts as well as certain physiological transcripts. We are carrying out studies to further elucidate the relationships between NMD, RNA splicing and R loops, and to test the therapeutic potential of targeting NMD for the treatment of MDS and cancer with spliceosome mutations, using both cultured cells and animal models.

Youlab Merged (002)

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

Recent publications

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; doi:1158/0008-5472.

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.

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

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

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

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

Chen X, Kim IK, Honaker Y, Paudyal SC, Koh W, Sparks M, Li S, Piwnica-Worms H, Ellenberger T and You Z.  14-3-3 Proteins Restrain the Exo1 Nuclease to Prevent Over-resection. Journal of Biological Chemistry 2015; 290 (19): 12300-12312.

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

Chen X, Paudyal SC, Chin RI and You Z.  PCNA promotes processive DNA end resection by Exo1. Nucleic Acids Research 2013; 41(20): 9325-9338.

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.