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陳世勳 Dr. Shih-Hsun Chen

專任助理教授

  • IBS R302、R304
  • (02)33664067、(02)23665590
  • (02)23635038
  • shichen@ntu.edu.tw
  • DNA損傷修復相關疾病機制、電腦輔助藥物設計與研發
【學歷】
2014-01  國立交通大學  生物科技學系暨研究所 博士
 
【經歷】
2020 - 至今  國立臺灣大學 生化科學研究所 助理教授
2015 - 2020  美國希望之城醫學研究中心 (City of Hope) 博士後研究員
2014 - 2015  美國密西根大學 (University of Michigan, Ann Arbor) 博士後研究員
2014 - 2014  中央研究院 生物化學研究所 博士後研究員（科技部）
 
   【研究方向】
Research interests of our laboratory
Our research interests focus on exploring the mechanisms of DNA repair and treatments of DNA repair-related diseases (such as cancer, aging, neurodegenerative diseases, etc.) Based on mechanistic studies, we will identify small-molecule drugs or novel strategies for the treatments of human diseases. The topics are divided into four directions:
1. Investigations of DNA repair mechanisms (DNA損傷修復機制研究)
2. Computer-aided drug design and discovery (電腦輔助藥物設計與研發)
3. Tumorigenesis and cancer therapies (癌症機轉研究與治療)
4. Mechanism-based drug discovery for anti-aging and -neurodegenerative diseases (抗老化及神經退化疾病之藥物研發)  

DNA repair is closely related to human diseases 
DNA damage often occurs in the cells of every person's body. What causes DNA damage in our cells? There are two main sources, one is exogenous factors (such as radiation, viral infection, and chemicals), the other is endogenous stresses that are from replication errors and cellular metabolism (such as reactive oxygen species). Once DNA damage occurs, it will affect cell cycle, transcription, DNA repair, and cell apoptosis. Because lots of single-stranded and double-stranded DNA will break in each cell cycle, even in every minute, and DNA damage involves in some important biological processes, it is associated with many human diseases, such as immunological disorders, cancer, aging, and neurological disorders. Thus, DNA repair is very important when DNA damage occurs. DNA repair defects will cause gene instability and the occurrence of diseases (Figure 1).


Figure 1. Loss of DNA repair causes many human diseases, including tumorigenesis, aging, neurodegenerative diseases etc.

Post-translational modifications are important for DNA repair
Post-translational modifications, such as protein phosphorylation, ADP-ribosylation, ubiquitination, acetylation, and methylation, are important for numerous biological processes, including DNA damage response. It has been reported that protein phosphorylation, ADP-ribosylation, and ubiquitination facilitate DNA single-strand break (SSB) and/or double-strand break (DSB) repair. Numerous studies investigating ADP-ribosylation have been performed in the last several decades. Yet, our understanding of the molecular mechanisms governing ADP-ribosylation signaling and the physiological and pathophysiological importance of the pathways regulated by ADP-ribosylation are still poorly understood. Thus, there are many exciting findings waiting to be discovered in this field of research. For example, the enzymatic activities of “ADP-ribosylation erasers” have been studied but their biological functions in DNA damage response are still unclear (Figure 2). Moreover, the relationship between ubiquitination, acetylation or methylation and DNA repair is also worth further investigating.

Figure 2. mono- and poly-ADP-ribosylation play an important role for DNA repair

Mechanism-based drug discovery for DNA repair-related human diseases
Our previous study shows that BRCA-deficient breast and ovarian cancer cells are hypersensitive to the treatment of PARG inhibitor, COH34 (Figure 3). Thus, similar to PARP and PARG inhibitor, small molecules that suppress DNA repair are able to be utilized for cancer chemotherapy. In particular, PARP inhibitor has been applied in the clinical treatment of cancers with BRCA mutation. Thus, we plan to examine if DNA repair-defective breast, ovarian, lung, colon, and pancreatic cancers are hypersensitive to these small molecules identified by our in silico strategies. In addition to cancer, DNA repair is also associated with aging and neurodegenerative diseases. The new drug targets and small-molecule regulators for anti-aging and neurodegenerative diseases will be identified based on mechanistic studies. We expect that our studies could be applied for clinical treatments in the future.



Figure 3. Using in silico strategy with siMMap analysis to identify novel PARG inhibitor (COH34) for DNA repair-defective cancer treatments.

【期刊著作】
2022 Chen, Q.#; Ma, K.#; Liu, X.; Chen, S. H.; Li, P.; Yu, Y.; Leung, A. K.L.; Yu, X.*, Truncated PARP1 mediates ADP-ribosylation of RNA polymerase III for apoptosis. Cell Discovery 2022, 8(1), 3. (# Equal contribution) (IF: 38.079, RF: 3.6%)
2021 Zhao, F. #; Kim, W. #; Gao, H.; Liu, C.; Zhang, Y.; Chen, Y.; Deng, M.; Zhou, Q.; Huang, J.; Hu, Q.; Chen, S. H.; Nowsheen, S.; Kloeber, J. A.; Qin, B.; Yin, P.; Tu, X.; Guo, G.; Qin, S.; Zhang, C.; Gao, M.; Luo, K.; Liu, Y.; Lou, Z.*; Yuan, J.*, ASTE1 promotes shieldin-complex-mediated DNA repair by attenuating end resection. Nature Cell Biology 2021, 23(8), 894–904. (IF: 28.824, RF: 2.6%) (# Equal contribution)
2020 Liu, X. #, Xie, R. #, Yu, L. #, Chen, S. H. #, Yang, X., Singh, A. K., Li, H., Wu, C., Yu, X.*, AI26 inhibits the ADP-ribosyl hydrolase ARH3 and suppresses DNA damage repair. The Journal of Biological Chemistry 2020, 295(40), 13838–13849. (# Equal contribution) (IF: 4.238, RF: 29%)
Yang, G. #; Chen, Y. #; Wu, J.; Chen, S. H.; Liu, X.; Yu, X.*, Poly(ADP-ribosyl)ation mediates early phase histone eviction at DNA lesions. 2020, 48(6), 3001-3013. Nucleic Acids Research (IF: 11.501, RF: 5%) (# Equal contribution)
2019 Chen, S. H.; Yu, X.*, Targeting dePARylation selectively suppresses DNA repair-defective and PARP inhibitor-resistant malignancies. Science Advances 2019, 5, eaav4340. (IF: 13.116, RF: 5.6%)
Chen, S. H.; Yu, X.*, Human DNA ligase IV is able to use NAD+ as an alternative adenylation donor for DNA ends ligation. Nucleic Acids Research 2019, 47(3), 1321-1334. (IF: 11.501, RF: 5%)
Bian, C.#; Zhang, C. #; Luo, T. #; Vyas, A.; Chen, S. H.; Liu, C.; Kassab, M. A.; Yang, Y.; Kong, M.; Yu, X.*, NADP+ is an endogenous PARP inhibitor in DNA   damage response and tumor suppression. Nature Communications 2019, 10, 693. (# Equal contribution) (IF: 12.121, RF: 8.5%)
Hou, W. H.; Chen, S. H.; Yu, X.*, Poly-ADP ribosylation in DNA damage response and cancer therapy. Mutation Research/Reviews in Mutation Research 2019, 780, 82-91. (IF: 5.803, RF: 7.6%)
2018 Yang, G.; Liu, C.; Chen, S. H.; Kassab, M. A.; Hoff, J. D.; Walter, N. G.; Yu, X.*, Super-resolution imaging identifies PARP1 and the Ku complex acting as DNA    double-strand break sensors. Nucleic Acids Research 2018, 46(7), 3446-3457. (IF: 11.501, RF: 5%)
2015 Zhang, F. #; Shi, J. #; Chen, S. H.; Bian, C.; Yu, X.*, The PIN domain of EXO1 recognizes poly(ADP-ribose) in DNA damage response. Nucleic Acids Research 2015, 43(22), 10782-10794. (# Equal contribution) (IF: 11.501, RF: 5%)
2014 Kumar, V.; Chang, C. K.; Tan, K. P.; Jung, Y. S.; Chen, S. H.; Cheng, Y. S. E.; Liang, P. H.*, Identification, Synthesis, and Evaluation of New Neuraminidase Inhibitors. Organic Letters 2014, 16(19), 5060-5063. (IF: 6.091, RF: 7%)
2013 Chen, S. H.; Lin, S. W.; Lin, S. R.; Liang, P. H.*; Yang, J. M.*, Moiety-linkage map reveals selective nonbisphosphonate inhibitors of human geranylgeranyl diphosphate synthase. Journal of Chemical Information and Modeling 2013, 53(9), 2299-2311. (IF: 4.549, RF: 15.6%)
Lin, Y. F.; Lai, T. C.; Chang, C. K.; Chen, C. L.; Huang, M. S.; Yang, C. J.; Liu, H. G.; Dong, J. J.; Chou, Y. A.; Teng, K. H.; Chen, S. H.; Tian, W. T.; Jan, Y. H.; Hsiao, M.; Liang, P. H.*, Targeting the XIAP/caspase-7 complex selectively kills caspase-3-deficient malignancies. The Journal of Clinical Investigation 2013,123(9), 3861-3875. (IF: 11.864, RF: 2.2%)
Al-Mudaris, Z. A. #; Majid, A. S. #; Ji, D. #; Al-Mudarris, B. A.; Chen, S. H.; Liang, P. H.; Osman, H.; Jamal Din, S. K.; Abdul Majid, A. M.*, Conjugation of benzylvanillin and benzimidazole structure improves DNA binding with enhanced antileukemic properties. PloS one 2013, 8(11), e80983. (# Equal contribution) (IF: 2.74, RF: 38%)
2012 Chang, K. M. #; Chen, S. H. #; Kuo, C. J.; Chang, C. K.; Guo, R. T.; Yang, J. M.; Liang, P. H.*, Roles of amino acids in the Escherichia coli octaprenyl diphosphate synthase active site probed by structure-guided site-directed mutagenesis. Biochemistry 2012, 51(16), 3412-3419. (# equal contribution) (IF: 2.865, RF: 57%)
2009 Lo, C. H.; Chang, Y. H.; Wright, J. D.; Chen, S. H.; Kan, D.; Lim, C.; Liang, P. H.*, Combined experimental and theoretical study of long-range interactions modulating dimerization and activity of yeast geranylgeranyl diphosphate synthase. Journal of the American Chemical Society 2009, 131(11), 4051-4062. (IF: 14.612, RF: 7.3%)