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Shen-Binghui

Binghui Shen, Ph.D.

  • Chair and Professor, Department of Cancer Genetics and Epigenetics
  • Co-leader, Molecular Oncology Program, Comprehensive Cancer Center

Binghui Shen, Ph.D.

Research Focus :
  • Cancer Genetics and Epigenetics
RESEARCH_TEAM :
  • Cancer Genetics and Epigenetics
  • Molecular and Cellular Biology of Cancer Program
  • Comprehensive Cancer Center Co-leaders
  • Program in Natural Therapies

Degrees

  • 1991, Kansas State University, Manhattan, Kansas Ph.D. Molecular Genetics
  • 1983, Zhejiang University, Hangzhou, P.R. China B.S. Biology

Fellowship

  • 1994-1996, Los Alamos National Laboratory, Los Alamos, NM Postdoctoral Fellow - Molecular Biology and Biochemistry
  • 1991-1994, University of California, Irvine, Irvine, CA Postdoctoral Fellow - Molecular Biology and Biochemistry
  •  ​DNA replication and repair nucleases and cancer etiological models

Our initial research emphasis was on nucleases, which play critical roles in DNA replication and repair as strong mutator genes and cancer etiological factors. In particular, we  focus on FEN1, the founding member of the structure specific nuclease family. One of the most interesting questions in the field was which structural elements enable this family of nucleases to recognize DNA/RNA substrates based on their structural conformations rather than specific DNA sequence motifs. Using X-ray crystallography and mutation analysis we have identified key structural elements that facilitate substrate recognition, binding, cleavage and dissociation. The other significant aspect of our research has been to address how sequential polymerase/nuclease/ligase reactions are correctly timed as factors bind to the DNA replication fork. We found that sequential posttranslational modificiations of FEN1 are critical for its timed activity, localization, and fate during the cell cycle. We have also established a series of etiological mouse models for FEN1 mutations identified in human cancer patients and made them available to the research community for molecular mechanistic studies and cancer drug tests.

Meanwhile we have made important contribution to elucidate the biological functional roles of the other nuclease family member, DNA2. We were the first to demonstrate that the nuclear DNA-encoded nuclease DNA2 predominantly migrates to mitochondrion, plays an important role in mitochondrial DNA replication and oxidative DNA damage repair, and is a major etiological factor for the familian mitochondrion mediated myopathy. We deleted the DNA2 gene in mouse genome and revealed that DNA2 is required for maintaining the integrity of telomeres and resolves G-quadruplexes.

  • Histone modifiers

During the identification and characterization of multiple posttranslational modifications of FEN1, a surprising result led us to identify a novel arginine demethylase and spurred our new research program in cancer epigenetics. For the last three years, we have systematically collected necessary experimental materials such as histone tail peptides that are methylated at different sites, antibodies and a panel of histone demethylases. We have established key techniques needed to study histone modifications, such as mass spectrometry and hematopoietic stem cell culturing, manipulation and sorting.

We have recently also found that ubiquitin ligase, ITCH, is highly over expressed in response to DNA replication stresses and specifically modifies the histone variants. We are currently investigating how this series of events facilitate the breast cancer metastasis.

Li Zheng, Ph.D.

Assistant Res. Professor

[email protected]

Zhengke Li, Ph.D.

Postdoc Fellow

[email protected]

Mian Zhou, M.D., Ph.D.

Staff Scientist

[email protected]

Shafat Ali, Ph.D.

Postdoc Fellow

[email protected]

Huifang Dai, B.S.

Senior Res. Associate

[email protected]

Lina Zhou, B.S.

Research Assistant

[email protected]

Fong-Fong Chu, Ph.D.

Staff Scientist

[email protected]

Lufen Chang, Ph.D.

Assistant Res.

Professor

[email protected]

R. Steve Esworthy, Ph.D.

Staff Scientist

[email protected]

Sophia Pan, B.S.

Research Assistant

[email protected]

 

 

Selected publications
 
1. Chapados, B., Hosfield, D.J., Han, S., Qiu, J., Yelent, B, Shen, B., Tainer, J.A. (2004) Structural basis for FEN-1 substrate recognition and PCNA-mediated exchange in replication and repair.  Cell, 116, 39-50. PMID: 14718165.
 
2. Zheng, L., Zhou, M., Chai, Q., Patrick, S. M., Turchi, J.J., Parrish, J., Xue, D., Yannone, S., Chen, D., and Shen, B. (2005) Novel roles of flap endonuclease-1 complex in processing stalled replication forks. EMBO Reports, 6, 83-89. PMCID: PMC1299223
 
3. Zheng, L., Dai, H., Zhou, M., Li, M., Singh, P., Qiu, J., Tsark, W., Huang, Q., Kernstine, K, Zhang, X., Lin, D, and Shen, B. (2007) Fen1 mutations results in autoimmunity, chronic inflammation, and cancers.
Nature Medicine, 13, 812-819. PMID: 17589521
 
4. Guo, Z., Qian, L., Liu, R., Dai, H., Zhou, M., Zheng, L., and Shen, B. (2008) Nucleolar localization and dynamic roles of flap endonuclease1 in ribosomal DNA replication and damage repair. Mol. Cell. Biol. 28, 4310-4319. PMCID: PMC2447149
 
5. Zheng L., Zhou, M., Dai, H., Guo, Z., Lu, M., Qiu, J., Bogenhagen, and Shen, B. (2008) Human DNA2 is a mitochondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates, in complex with polymerase  and flap endonuclease 1,  Molecular Cell, 32, 325-336. PMCID: PMC2636562
 
6. Finger, L.D., Blanchard, M.S., Theimer, C.A., Sengerova, B., Singh, P., Chavez, V., Liu, F., Grasby, J.A., and Shen, B. (2009) The 3’-flap pocket of human flap endonuclease 1 is critical for substrate binding and catalysis. J. Biol. Chem. 284, 22184-22194. PMCID: PMC2755943
 
7. Guo, Z., Zheng, L., Xu, H., Dai, H., Zhou, M., Pascua, M. R., Chen, Q. M., and Shen, B. (2010) Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding. Nature Chem. Biol. 6, 766-773. DOI: 10.1038.  PMCID: PMC2943039
 
8. Tsutakawa, S.E., Classen, S., Chapados, B.R., Arval, A., Finger, L.D., Guenther, G., Tomlinson, C.G., Thompson, P., Sarker, A.H., Shen, B., Cooper, P.K., Grasby, J.A., and Tainer, J.A. (2011) Human flap endonuclease structures, DNA double base flipping and a unified understanding of the FEN1 superfamily. Cell, 145, 198-211. PMCID: PMC3086263
 
9. Zheng, L., Dai, H., Zhou, M., Li, X., Guo, Z., Wu, X., Wu, J., Wang, C., Zhong, J., Huang, Q., Garcia-Aguilar, J., Pfeifer, G., and Shen, B. (2012) Polyploidy rewires DNA damage response and repair network to overcome DNA replication stresses and to escape cellular senescence, Nature Communications., 3, 815-826. PMCID: PMC3517178
 
10. Guo, Z., Kanjanapangka, J., Liu, N., Liu, S., Liu, C., Wu, Z., Wang, Y., Loh., T., Kowolik, C., Jamsen, J., Zhou, M., Truong, K., Chen, Y., L. Zheng, Shen, B. (2012), Sequential post-translational modifications program FEN1 degradation during cell-cycle progression, Molecular Cell, 47 444-456. PMCID: PMC3518404
 
11. Ronchi, D., Di Fonzo, A., Lin, W., Bordoni, A., Liu, C., Fassone, E., Pagliarani, S., Rizzuti, M., Zheng, L., Filosto, M., Ferrò, M. T., Ranieri, M., Magri, F., Corti, S., Sciacco, H. Li, Y.-C. Yuan, M., Moggio, M., Bresolin, N., Shen, B.*, and Comi, G. P.* (2013) Mutations in DNA2 link progressive myopathy with mitochondrial DNA instability. American Journal of Human Genetics, 92, 293-300. Co-corresponding authors. PMID: 23352259
 
12. Lin, W., Sampathi, S., Dai, H., Liu, C., Zhou, M., Hu, J., Huang, Q., Campbell, J., Zheng, L., Chai, W., Shen, B. (2013) Mammalian DNA2 helicase/nuclease cleaves G-quadruplex and is required for telomere integrity. EMBO J., 32, 1425-1439. PMCID: PMC3655473
 
13. Wang, H., Li, Y., Truong, L.N., Shi, L.Z., Hwang, P.Y., He, J., Do, J., Cho, M.J., Li, H., Negrete, A., Shiloach, J., Berns, M.W., Shen, B., Chen, L., and Wu, X. CtIP maintains stability at common fragile sites and inverted repeats by an end resection-independent endonuclease activity, Molecular Cell, 54, 1012-1021.
 
14. Chung, L., Onyango, D., Guo, Z., Jia, P., Dai, H., Liu, S., Zhou, M., Lin, W., Pang, I., Li, H., Yuan,   Y.-C., Huang, Q., Zheng, L., Lopes, J., Nicolas, A., Chai, W., Raz, D., Reckamp, K.L., and Shen, B. (2015) The FEN1 E359K germline mutation disrupts the FEN1-WRN interaction and FEN1 GEN activity, causing aneuploidy-associated cancers. Oncogene, 34, 902-911.
 
15. Liu, S., Lu, G., Ali, S., Liu, W., Zheng, L., Dai, H., Li, H., Xu, H., Hua, Y., Zhou, Y.,  Ortega, J., Li, G., Kunkel, T.A., and Shen, B. (2015) Okazaki fragment maturation involves α-segment error editing by the mammalian FEN1/MutSα functional complex.  EMBO J., 34, 1829-1843. DOI: 0.15252/EMBOJ.201489865 
 
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