Zhongsheng You, PhD
Professor
Cell Biology and Physiology
Internal Medicine
Molecular Cell Biology Program
Molecular Genetics and Genomics Program
Biochemistry, Biophysics, and Structural Biology Program
Cancer Biology Program
314-362-9893
314-362-4668
314-422-5223 (cell)
314-362-7463
McDonnell Sciences Building, Room 514
zyou@wustl.edu
http://sites.wustl.edu/youlab
cancer, replication stress response, DNA damage response, nonsense-mediated RNA decay, genetically-encoded reporters, cell imaging
DNA and RNA surveillance mechanisms and their relation to cancer formation and treatment
Research Abstract:
Our laboratory is interested in understanding DNA and RNA surveillance systems in human cells and their relation to diseases, especially cancer. In DNA surveillance, we focus on the replication stress response and DNA double-strand break (DSB) damage response, both of which are essential for genome maintenance and are being actively exploited for cancer treatment. Our work in the DSB damage response has led to major findings in several key biochemical processes, including ATM activation and DNA end resection, that are crucial for mounting an effective stress response for proper DNA repair in cells. More recently, we have discovered a novel Ca2+-dependent signaling pathway that is activated by replication stress for the protection of replication fork structure and chromosomal stability. We are currently further characterizing this pathway and exploring its functions beyond replication fork protection.
In the RNA surveillance area, we focus on nonsense-mediated RNA decay (NMD), an RNA quality control pathway that targets aberrant mRNAs harboring premature translation termination codons for degradation. By using innovative reporter systems developed in the lab as well as other tools, we have found that NMD activity is regulated by intracellular Ca2+ and by persistent DNA damage. Additionally, we have discovered a synthetic lethal relationship between NMD inhibition and mutations in spliceosome factors such as SF3B1 and U2AF1. This finding suggests that NMD is an attractive target for treating cancers with spliceosome mutations, which are common in many hematological malignancies (e.g. MDS, AML, CMML). We are currently carrying out preclinical studies in animal models in collaboration with our colleagues to further test the potential of this strategy, with the goal of developing effective NMD-targeting cancer therapeutics.
Mentorship and Commitment to Diversity Statement:
We believe that diversity and inclusion are key to scientific advancement and personal development, and we are committed to creating a stimulating and supportive environment for research and training.
Selected Publications:
Yang Z, Lemacon DS, Li S, Cheruiyot A, Kong L, Tan K, Cheng C, Turkay E, He D and You Z. A Context-dependent Pro- and Anti-resection Roles of ZKSCAN3 in Regulating Fork Resection during Replication Stress. Journal of Biological Chemistry 2022. 29:102215.
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.
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 K, Piwnica-Worms, D, Stewart S 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 Suppresses Its Nuclease Activity. DNA Repair 2015, 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. 14-3-3 Proteins Restrain the Exo1 Nuclease to Prevent Over-resection. Journal of Biological Chemistry 2015, 290: 12300-12.
Nickless A, Jackson E, Marasa J, Mercer RW, Piwnica-Worms D*, You Z*. Intracellular calcium regulates nonsense-mediated mRNA decay. Nature Medicine 2014, 20(8): 961-966.
Chen X, Paudyal SC, Chin RI, You Z. PCNA promotes processive DNA end resection by Exo1. Nucleic Acids Research 2013, 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*. CtIP Links DNA Double-strand Break Sensing to Resection. Molecular Cell 2009, 36:954-969.
You Z, Bailis J, Johnson S, Dilworth S and Hunter T. Rapid Activation of ATM on DNA Flanking Double-Strand Breaks, Nature Cell Biology 2007, 9:1311-1318.
Last Updated: 1/4/2023 12:23:33 PM