An NCI-designated Comprehensive Cancer Center
Shen-Binghui

Binghui Shen, Ph.D.

Professor and Chair, Department of Cancer Genetics and Epigenetics
Research Focus
  • Enzymology of DNA Replication and Repair
  • Genomic Instability
Appointments
Co-leader, Molecular and Cellular Biology of Cancer Program, Comprehensive Cancer Center; Co-director, NCI-funded T32 Progrm
Contact
Email: [email protected]
The Shen laboratory is focused on understanding the cellular mechanisms that maintain and disrupt genomic stability. Genomic instability contributes to many diseases, particularly cancer. The genome is especially vulnerable during DNA replication. The replisome stalls at DNA lesions and under replication stress, and unstable stalled replication forks may be aberrantly processed, leading to double-strand break formation and chromosomal rearrangements. Thus, cells must rapidly stabilize stalled forks and initiate a pathway to restart and complete DNA replication.
 
Our lab studies the mechanisms underlying DNA replication and DNA damage response and repair in normal and cancer cells using multidisciplinary techniques, including biochemical, cellular, structural biological, and chemical approaches, as well as genetic mouse modeling. We aim to understand how DNA damage response and repair processes are initiated, timed, and efficiently implemented with high fidelity, initially using the structure-specific nucleases FEN1 and DNA2 as model molecules. In parallel, we are working to elucidate the ways in which germline and somatic mutations affect the DNA damage response and repair pathways to promote cancer initiation.
 

Locations

City of Hope Comprehensive Cancer Center, 1500 East Duarte Road

Duarte, CA 91010

  • Li, Z., Liu, B., Jin, W., Wu, X., Liu, V. W., Shen, Z., Zheng, L., and Shen, B. (2018) hDNA2 helicase/nuclease promotes centromeric DNA replication and genome stability. (2018) The EMBO Journal e96729. DOI10.15252/embj.201796729|Published online 17.05.2018
  • Li, S., Ali, S., Duan, X., Liu, S., Du,J., Liu, C., Dai, H., Zhou, M., Zhou, L., Yang, L., Chu, P., Li, L., Bhatia, R., Schones, D. E., Wu, X., Xu, H., Hua, Y., Guo, Z., Yang, Y., Zheng, L., and Shen, B. (2018) JMJD1B Demethylates H4R3me2s and H3K9me2 to Facilitate Gene Expression for Development of Hematopoietic Stem and Progenitor Cells. Cell Reports 23, 389–403. DOI: https://doi.org/10.1016/j.celrep.2018.03.051.
  • Ray-Chaudhuri A, Callen E., Ding X., Gogola E., Duarte AA., Lee, JE, Wong, N., Lafarga, V., Calvo, JA., Panzarino, NJ., John, S., Day, A., Crespo, AV., Shen, B., Starnes, LM., de Ruiter, JR., Daniel, JA., Konstantinopoulos, PA., Cortez, D., Cantor, SB., Fernandez-Capetillo, O., Ge, K., Jonkers, J., Rottenberg, S.,Sharan, SK., Nussenzweig, A., (2016) Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature, 535, 382-7. doi: 10.1038/nature18325. PMCID: PMC4959813
  • Liu, S., Lu, G., Ali, S., Liu, W., Zheng, L., Dai, H., Li, H., Xu, H., Hua, Y., Zhou, Y., Ortega, J., Li, G.-M., Kunkel, T.A. and Shen, B. (2015) Okazaki fragment maturation involves αalpha-segment error editing by the mammalian FEN1/MutSα functional complex. EMBO J., 34, 1829-1843. DOI: 10.15252/EMBOJ.201489865; PMCID: PMC4516434
  • 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. (2014) CtIP maintains stability at common fragile sites and inverted repeats by an end resection-independent endonuclease activity. Molecular Cell, 54, 1012-1021. PMCID: PMC4105207
  • 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
  • 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.*, & 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. PMCID: PMC3567272
  • 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
  • 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., & 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
  • Guo, Z., Zheng, L., Xu, H., Dai, H., Zhou, M., Pascua, M. R., Chen, Q. M., & Shen, B. (2010). Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding. Nature Chem. Biol. 6, 766-773. DOI: 10.1038.  PMCID: PMC2943039
  • Zheng L., Zhou, M., Dai, H., Guo, Z., Lu, M., Qiu, J., Bogenhagen, & Shen, B. (2008). Human DNA2 is a mitochondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates, in complex with polymerase gamma and flap endonuclease 1, Molecular Cell, 32, 325-336. PMCID: PMC2636562
  • Zheng, L., Dai, H., Zhou, M., Li, M., Singh, P., Qiu, J., Tsark, W., Huang, Q., Kernstine, K, Zhang, X., Lin, D, & Shen, B. (2007). Fen1 mutations results in autoimmunity, chronic inflammation, and cancers. Nature Medicine, 13, 812-819. PMID: 17589521
  • 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.
  • Hosfield, D., Mol, C. D., Shen, B. & Tainer, J. A. (1998) Crystal structure of the DNA repair and replication exo- and endonuclease FEN-1: Implications for coupling DNA and PCNA binding to enzymatic activity. Cell, 95, 135-146. PMID: 9778254
  • Shen, B., Qiu, J., Hosfield, D., and Tainer, J. A. (1998) Flap endonuclease homologues in archaebacteria exist as independent proteins. TiBS, 23, 171-173.
 
In The News