Binghui Shen

Beckman Research Institute, Дуарте, California, United States

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Publications (70)518.23 Total impact

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    ABSTRACT: Drug resistance is a major challenge in cancer therapeutics. Abundant evidence indicates that DNA repair systems are enhanced after repetitive chemotherapeutic treatments, rendering cancers cells drug-resistant. Flap endonuclease 1 (FEN1) plays critical roles in DNA replication and repair and in counteracting replication stress, which is a key mechanism for many chemotherapeutic drugs to kill cancer cells. FEN1 was previously shown to be upregulated in response to DNA damaging agents. However, it is unclear about the transcription factors that regulate FEN1 expression in human cancer. More importantly, it is unknown whether up-regulation of FEN1 has an adverse impact on the prognosis of chemotherapeutic treatments of human cancers. To reveal regulation mechanism of FEN1 expression, we search and identify FEN1 transcription factors or repressors and investigate their function on FEN1 expression by using a combination of biochemical, molecular, and cellular approaches. Furthermore, to gain insights into the impact of FEN1 levels on the response of human cancer to therapeutic treatments, we determine FEN1 levels in human breast cancer specimens and correlate them to the response to treatments and the survivorship of corresponding breast cancer patients. We observe that FEN1 is significantly up-regulated upon treatment of chemotherapeutic drugs such as mitomycin C (MMC) and Taxol in breast cancer cells. We identify that the transcription factor/repressor YY1 binds to the FEN1 promoter and suppresses the expression of FEN1 gene. In response to the drug treatments, YY1 is dissociated from the FEN1 promoter region leading over-expression of FEN1. Overexpression of YY1 in the cells results in down-regulation of FEN1 and sensitization of the cancer cells to MMC or taxol. Furthermore, we observe that the level of FEN1 is inversely correlated with cancer drug and radiation resistance and with survivorship in breast cancer patients. Altogether, our current data indicate that YY1 is a transcription repressor of FEN1 regulating FEN1 levels in response to DNA damaging agents. FEN1 is up-regulated in human breast cancer and its levels inversely correlated with cancer drug and radiation resistance and with survivorship in breast cancer patients.
    BMC Cancer 12/2015; 15(1):1043. DOI:10.1186/s12885-015-1043-1 · 3.32 Impact Factor
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    ABSTRACT: During nuclear DNA replication, proofreading-deficient DNA polymerase α (Pol α) initiates Okazaki fragment synthesis with lower fidelity than bulk replication by proofreading-proficient Pol δ or Pol ε. Here, we provide evidence that the exonuclease activity of mammalian flap endonuclease (FEN1) excises Pol α replication errors in a MutSα-dependent, MutLα-independent mismatch repair process we call Pol α-segment error editing (AEE). We show that MSH2 interacts with FEN1 and facilitates its nuclease activity to remove mismatches near the 5' ends of DNA substrates. Mouse cells and mice encoding FEN1 mutations display AEE deficiency, a strong mutator phenotype, enhanced cellular transformation, and increased cancer susceptibility. The results identify a novel role for FEN1 in a specialized mismatch repair pathway and a new cancer etiological mechanism. © 2015 The Authors.
    The EMBO Journal 04/2015; DOI:10.15252/embj.201489865 · 10.75 Impact Factor
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    ABSTRACT: Chromosomal rearrangements often occur at genomic loci with DNA secondary structures, such as common fragile sites (CFSs) and palindromic repeats. We developed assays in mammalian cells that revealed CFS-derived AT-rich sequences and inverted Alu repeats (Alu-IRs) are mitotic recombination hotspots, requiring the repair functions of carboxy-terminal binding protein (CtBP)-interacting protein (CtIP) and the Mre11/Rad50/Nbs1 complex (MRN). We also identified an endonuclease activity of CtIP that is dispensable for end resection and homologous recombination (HR) at I-SceI-generated "clean" double-strand breaks (DSBs) but is required for repair of DSBs occurring at CFS-derived AT-rich sequences. In addition, CtIP nuclease-defective mutants are impaired in Alu-IRs-induced mitotic recombination. These studies suggest that an end resection-independent CtIP function is important for processing DSB ends with secondary structures to promote HR. Furthermore, our studies uncover an important role of MRN, CtIP, and their associated nuclease activities in protecting CFSs in mammalian cells.
    Molecular Cell 05/2014; 54(6). DOI:10.1016/j.molcel.2014.04.012 · 14.46 Impact Factor
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    Weihang Chai, Li Zheng, Binghui Shen
    Cell cycle (Georgetown, Tex.) 06/2013; 12(13). DOI:10.4161/cc.25306 · 5.01 Impact Factor
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    ABSTRACT: Efficient and faithful replication of telomeric DNA is critical for maintaining genome integrity. The G-quadruplex (G4) structure arising in the repetitive TTAGGG sequence is thought to stall replication forks, impairing efficient telomere replication and leading to telomere instabilities. However, pathways modulating telomeric G4 are poorly understood, and it is unclear whether defects in these pathways contribute to genome instabilities in vivo. Here, we report that mammalian DNA2 helicase/nuclease recognizes and cleaves telomeric G4 in vitro. Consistent with DNA2's role in removing G4, DNA2 deficiency in mouse cells leads to telomere replication defects, elevating the levels of fragile telomeres (FTs) and sister telomere associations (STAs). Such telomere defects are enhanced by stabilizers of G4. Moreover, DNA2 deficiency induces telomere DNA damage and chromosome segregation errors, resulting in tetraploidy and aneuploidy. Consequently, DNA2-deficient mice develop aneuploidy-associated cancers containing dysfunctional telomeres. Collectively, our genetic, cytological, and biochemical results suggest that mammalian DNA2 reduces replication stress at telomeres, thereby preserving genome stability and suppressing cancer development, and that this may involve, at least in part, nucleolytic processing of telomeric G4.
    The EMBO Journal 04/2013; DOI:10.1038/emboj.2013.88 · 10.75 Impact Factor
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    ABSTRACT: Syndromes associated with multiple mtDNA deletions are due to different molecular defects that can result in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia (PEO) to multisystemic disorders of variable severity. The autosomal-dominant form of PEO is genetically heterogeneous. Recently, causative mutations have been reported in several nuclear genes that encode proteins of the mtDNA replisome machinery (POLG, POLG2, and C10orf2) or that are involved in pathways for the synthesis of deoxyribonuclotides (ANT1 and RRM2B). Despite these findings, putative mutations remain unknown in half of the subjects with PEO. We report the identification, by exome sequencing, of mutations in DNA2 in adult-onset individuals with a form of mitochondrial myopathy featuring instability of muscle mtDNA. DNA2 encodes a helicase/nuclease family member that is most likely involved in mtDNA replication, as well as in the long-patch base-excision repair (LP-BER) pathway. In vitro biochemical analysis of purified mutant proteins revealed a severe impairment of nuclease, helicase, and ATPase activities. These results implicate human DNA2 and the LP-BER pathway in the pathogenesis of adult-onset disorders of mtDNA maintenance.
    The American Journal of Human Genetics 01/2013; 92(2). DOI:10.1016/j.ajhg.2012.12.014 · 10.99 Impact Factor
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    ABSTRACT: The DNase domain-containing protein TATDN1 is a conserved nuclease in both prokaryotes and eukaryotes. It was previously implicated to play a role in apoptotic DNA fragmentation in yeast and C. elegans. However, its biological function in higher organisms, such as vertebrates, is unknown. Here, we report that zebrafish TATDN1 (zTATDN1) possesses a novel endonuclease activity, which first makes a nick at the DNA duplex and subsequently converts the nick into a DNA double-strand break in vitro. This biochemical property allows zTATDN1 to catalyze decatenation of catenated kinetoplast DNA to produce separated linear DNA in vitro. We further determine that zTATDN1 is predominantly expressed in eye cells during embryonic development. Knockdown of TATDN1 in zebrafish embryos results in an abnormal cell cycle progression, formation of polyploidy and aberrant chromatin structures. Consequently, the TATDN1-deficient morphants have disordered eye cell layers and significantly smaller eyes compared with the WT control. Altogether, our current studies suggest that zTATDN1 plays an important role in chromosome segregation and eye development in zebrafish.
    Cell cycle (Georgetown, Tex.) 11/2012; 11(24). DOI:10.4161/cc.22886 · 5.01 Impact Factor
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    Jeremy M Stark, Binghui Shen
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    ABSTRACT: Comment on: Karanja KK, et al. Cell Cycle 2012; 3983-96.
    Cell cycle (Georgetown, Tex.) 10/2012; 11(22). DOI:10.4161/cc.22605 · 5.01 Impact Factor
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    ABSTRACT: Signaling via the Akt serine/threonine protein kinase plays critical roles in the self-renewal of embryonic stem cells and their malignant counterpart, embryonal carcinoma cells (ECCs). Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG. Furthermore, in ECCs, unphosphorylated Oct4 bound to the AKT1 promoter and repressed its transcription. Phosphorylation of Oct4 by Akt resulted in dissociation of Oct4 from the AKT1 promoter, which activated AKT1 transcription and promoted cell survival. Therefore, a site-specific, posttranslational modification of the Oct4 protein orchestrates the regulation of its stability, subcellular localization, and transcriptional activities, which collectively promotes the survival and tumorigenicity of ECCs.
    Molecular cell 10/2012; 17(4). DOI:10.1016/j.molcel.2012.08.030 · 14.46 Impact Factor
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    ABSTRACT: We propose that cell-cycle-dependent timing of FEN1 nuclease activity is essential for cell-cycle progression and the maintenance of genome stability. After DNA replication is complete at the exit point of the S phase, removal of excess FEN1 may be crucial. Here, we report a mechanism that controls the programmed degradation of FEN1 via a sequential cascade of posttranslational modifications. We found that FEN1 phosphorylation stimulated its SUMOylation, which in turn stimulated its ubiquitination and ultimately led to its degradation via the proteasome pathway. Mutations or inhibitors that blocked the modification at any step in this pathway suppressed FEN1 degradation. Critically, the presence of SUMOylation- or ubiquitination-defective, nondegradable FEN1 mutant protein caused accumulation of Cyclin B, delays in the G1 and G2/M phases, and polyploidy. These findings may represent a newly identified regulatory mechanism used by cells to ensure precise cell-cycle progression and to prevent transformation.
    Molecular cell 06/2012; 47(3):444-56. DOI:10.1016/j.molcel.2012.05.042 · 14.46 Impact Factor
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    ABSTRACT: Mutations in genes involved in DNA replication, such as flap endonuclease 1 (FEN1), can cause single-stranded DNA breaks (SSBs) and subsequent collapse of DNA replication forks leading to DNA replication stresses. Persistent replication stresses normally induce p53-mediated senescence or apoptosis to prevent tumour progression. It is unclear how some mutant cells can overcome persistent replication stresses and bypass the p53-mediated pathways to develop malignancy. Here we show that polyploidy, which is often observed in human cancers, leads to overexpression of BRCA1, p19arf and other DNA repair genes in FEN1 mutant cells. This overexpression triggers SSB repair and non-homologous end-joining pathways to increase DNA repair activity, but at the cost of frequent chromosomal translocations. Meanwhile, DNA methylation silences p53 target genes to bypass the p53-mediated senescence and apoptosis. These molecular changes rewire DNA damage response and repair gene networks in polyploid tumour cells, enabling them to escape replication stress-induced senescence barriers.
    Nature Communications 05/2012; 3:815. DOI:10.1038/ncomms1825 · 10.74 Impact Factor
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    ABSTRACT: Human NEIL2, one of five oxidized base-specific DNA glycosylases, is unique in preferentially repairing oxidative damage in transcribed genes. Here we show that depletion of NEIL2 causes a 6-7-fold increase in spontaneous mutation frequency in the HPRT gene of the V79 Chinese hamster lung cell line. This prompted us to screen for NEIL2 variants in lung cancer patients' genomic DNA. We identified several polymorphic variants, among which R103Q and R257L were frequently observed in lung cancer patients. We then characterized these variants biochemically, and observed a modest decrease in DNA glycosylase activity relative to the wild type (WT) only with the R257L mutant protein. However, in reconstituted repair assays containing WT NEIL2 or its R257L and R103Q variants together with other DNA base excision repair (BER) proteins (PNKP, Polβ, Lig IIIα and XRCC1) or using NEIL2-FLAG immunocomplexes, an ~5-fold decrease in repair was observed with the R257L variant compared to WT or R103Q NEIL2, apparently due to the R257L mutant's lower affinity for other repair proteins, particularly Polβ. Notably, increased endogenous DNA damage was observed in NEIL2 variant (R257L)-expressing cells relative to WT cells. Taken together, our results suggest that the decreased DNA repair capacity of the R257L variant can induce mutations that lead to lung cancer development.
    DNA repair 04/2012; 11(6):570-8. DOI:10.1016/j.dnarep.2012.03.005 · 3.36 Impact Factor
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    ABSTRACT: Processing of Okazaki fragments to complete lagging strand DNA synthesis requires coordination among several proteins. RNA primers and DNA synthesised by DNA polymerase α are displaced by DNA polymerase δ to create bifurcated nucleic acid structures known as 5'-flaps. These 5'-flaps are removed by Flap Endonuclease 1 (FEN), a structure-specific nuclease whose divalent metal ion-dependent phosphodiesterase activity cleaves 5'-flaps with exquisite specificity. FENs are paradigms for the 5' nuclease superfamily, whose members perform a wide variety of roles in nucleic acid metabolism using a similar nuclease core domain that displays common biochemical properties and structural features. A detailed review of FEN structure is undertaken to show how DNA substrate recognition occurs and how FEN achieves cleavage at a single phosphate diester. A proposed double nucleotide unpairing trap (DoNUT) is discussed with regards to FEN and has relevance to the wider 5' nuclease superfamily. The homotrimeric proliferating cell nuclear antigen protein (PCNA) coordinates the actions of DNA polymerase, FEN and DNA ligase by facilitating the hand-off intermediates between each protein during Okazaki fragment maturation to maximise through-put and minimise consequences of intermediates being released into the wider cellular environment. FEN has numerous partner proteins that modulate and control its action during DNA replication and is also controlled by several post-translational modification events, all acting in concert to maintain precise and appropriate cleavage of Okazaki fragment intermediates during DNA replication.
    Sub-cellular biochemistry 01/2012; 62:301-26. DOI:10.1007/978-94-007-4572-8_16
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    ABSTRACT: Flap endonuclease 1 (FEN1), a member of the Rad2 nuclease family, possesses 5' flap endonuclease (FEN), 5' exonuclease (EXO), and gap-endonuclease (GEN) activities. The multiple, structure-specific nuclease activities of FEN1 allow it to process different intermediate DNA structures during DNA replication and repair. We previously identified a group of FEN1 mutations and single nucleotide polymorphisms that impair FEN1's EXO and GEN activities in human cancer patients. We also established a mouse model carrying the E160D FEN1 mutation, which mimics the mutations seen in humans. FEN1 mutant mice developed spontaneous lung cancer at high frequency at their late life stages. An important unanswered question is whether individuals carrying such FEN1 mutation are more susceptible to tobacco smoke and have an earlier onset of lung cancer. Here, we report our study on E160D mutant mice exposed to benzo[α]pyrene (B[α]P), a major DNA damaging compound found in tobacco smoke. We demonstrate that FEN1 employs its GEN activity to cleave DNA bubble substrates with BP-induced lesions, but the E160D FEN1 mutation abolishes such activity. As a consequence, Mouse cells carrying the E160D mutation display defects in the repair of B[α]P adducts and accumulate DNA double-stranded breaks and chromosomal aberrations upon treatments with B[α]P. Furthermore, more E160D mice than WT mice have an early onset of B[α]P-induced lung adenocarcinoma. All together, our current study suggests that individuals carrying the GEN-deficient FEN1 mutations have high risk to develop lung cancer upon exposure to B[α]P-containing agents such as tobacco smoke.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 12/2011; 731(1-2):85-91. DOI:10.1016/j.mrfmmm.2011.11.009 · 4.44 Impact Factor
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    ABSTRACT: Early and accurate diagnosis of malignant melanoma is critical for patient survival. However, currently used diagnostic markers are insufficiently specific, which limits their utility. We aimed to identify molecular markers that are more specific to malignant melanoma, thereby aiding in melanoma diagnosis and treatment. A PCR-based suppression subtractive hybridization was used to identify capping protein Z-line α1, protein phosphatase 1 catalytic subunit β isoform (PP1CB), and casein kinase 1 α1 (CSNK1A1) as being differentially expressed between melanoma cells and normal melanocytes. Quantitative reverse transcription-PCR and western blot analysis confirmed that these genes were overexpressed in melanoma cells. In addition, immunohistochemical assays revealed that the expression of PP1CB and CSNK1A1 was significantly greater in human melanoma specimens than nevi (P<0.0001). Combined application of PP1CB and CSNK1A showed high sensitivity and specificity for melanoma. Thus, our data suggest that PP1CB and CSNK1A1 are potential biomarkers for distinguishing malignant melanoma from other melanocytic lesions. In addition, because capping protein Z-line α1, PP1CB, and CSNK1A1 are involved in cell motility, which underlies invasion and metastasis of human cancer; they may be novel targets for antimetastatic therapies as well.
    Melanoma research 05/2011; 21(4):335-43. DOI:10.1097/CMR.0b013e328346b715 · 2.10 Impact Factor
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    ABSTRACT: Flap endonuclease (FEN1), essential for DNA replication and repair, removes RNA and DNA 5' flaps. FEN1 5' nuclease superfamily members acting in nucleotide excision repair (XPG), mismatch repair (EXO1), and homologous recombination (GEN1) paradoxically incise structurally distinct bubbles, ends, or Holliday junctions, respectively. Here, structural and functional analyses of human FEN1:DNA complexes show structure-specific, sequence-independent recognition for nicked dsDNA bent 100° with unpaired 3' and 5' flaps. Above the active site, a helical cap over a gateway formed by two helices enforces ssDNA threading and specificity for free 5' ends. Crystallographic analyses of product and substrate complexes reveal that dsDNA binding and bending, the ssDNA gateway, and double-base unpairing flanking the scissile phosphate control precise flap incision by the two-metal-ion active site. Superfamily conserved motifs bind and open dsDNA; direct the target region into the helical gateway, permitting only nonbase-paired oligonucleotides active site access; and support a unified understanding of superfamily substrate specificity.
    Cell 04/2011; 145(2):198-211. DOI:10.1016/j.cell.2011.03.004 · 33.12 Impact Factor
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    ABSTRACT: DNA replication and repair are critical processes for all living organisms to ensure faithful duplication and transmission of genetic information. Flap endonuclease 1 (Fen1), a structure-specific nuclease, plays an important role in multiple DNA metabolic pathways and maintenance of genome stability. Human FEN1 mutations that impair its exonuclease activity have been linked to cancer development. FEN1 interacts with multiple proteins, including proliferation cell nuclear antigen (PCNA), to form various functional complexes. Interactions with these proteins are considered to be the key molecular mechanisms mediating FEN1's key biological functions. The current challenge is to experimentally demonstrate the biological consequence of a specific interaction without compromising other functions of a desired protein. To address this issue, we established a mutant mouse model harboring a FEN1 point mutation (F343A/F344A, FFAA), which specifically abolishes the FEN1/PCNA interaction. We show that the FFAA mutation causes defects in RNA primer removal and long-patch base excision repair, even in the heterozygous state, resulting in numerous DNA breaks. These breaks activate the G2/M checkpoint protein, Chk1, and induce near-tetraploid aneuploidy, commonly observed in human cancer, consequently elevating the transformation frequency. Consistent with this, inhibition of aneuploidy formation by a Chk1 inhibitor significantly suppressed the cellular transformation. WT/FFAA FEN1 mutant mice develop aneuploidy-associated cancer at a high frequency. Thus, this study establishes an exemplary case for investigating the biological significance of protein-protein interactions by knock-in of a point mutation rather than knock-out of a whole gene.
    Cell Research 03/2011; 21(7):1052-67. DOI:10.1038/cr.2011.35 · 11.98 Impact Factor
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    Li Zheng, Binghui Shen
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    ABSTRACT: Completion of lagging strand DNA synthesis requires processing of up to 50 million Okazaki fragments per cell cycle in mammalian cells. Even in yeast, the Okazaki fragment maturation happens approximately a million times during a single round of DNA replication. Therefore, efficient processing of Okazaki fragments is vital for DNA replication and cell proliferation. During this process, primase-synthesized RNA/DNA primers are removed, and Okazaki fragments are joined into an intact lagging strand DNA. The processing of RNA/DNA primers requires a group of structure-specific nucleases typified by flap endonuclease 1 (FEN1). Here, we summarize the distinct roles of these nucleases in different pathways for removal of RNA/DNA primers. Recent findings reveal that Okazaki fragment maturation is highly coordinated. The dynamic interactions of polymerase δ, FEN1 and DNA ligase I with proliferating cell nuclear antigen allow these enzymes to act sequentially during Okazaki fragment maturation. Such protein-protein interactions may be regulated by post-translational modifications. We also discuss studies using mutant mouse models that suggest two distinct cancer etiological mechanisms arising from defects in different steps of Okazaki fragment maturation. Mutations that affect the efficiency of RNA primer removal may result in accumulation of unligated nicks and DNA double-strand breaks. These DNA strand breaks can cause varying forms of chromosome aberrations, contributing to development of cancer that associates with aneuploidy and gross chromosomal rearrangement. On the other hand, mutations that impair editing out of polymerase α incorporation errors result in cancer displaying a strong mutator phenotype.
    Journal of Molecular Cell Biology 02/2011; 3(1):23-30. DOI:10.1093/jmcb/mjq048 · 8.43 Impact Factor
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    ABSTRACT: A critical observation in sporadic cancers is that not all individuals are equally prone to developing cancer following exposure to a given environmental carcinogen. Epidemiological studies have suggested that the difference in the timing of cancer onset in response to exogenous DNA damage is likely attributable to genetic variations, such as those associated with base excision repair (BER) genes. To test this long-standing hypothesis and elucidate how a genetic variation in the BER gene flap endonuclease 1 (FEN1) results in susceptibility to environment insults and causes cancer, we established a mutant mouse model carrying a point mutation (E160D) in Fen1. We demonstrate that the E160D mutation impairs the ability of FEN1 to process DNA intermediate structures in long-patch BER using nuclear extracts or reconstituted purified BER proteins. E160D cells were more sensitive to the base-damaging agents methylnitrosourea and hydrogen peroxide, leading to DNA strand breaks, chromosomal breakage and chromosome instabilities in response these DNA insults. We further show that E160D mice are significantly more susceptible to exposure to methylnitrosourea and develop lung adenocarcinoma. Thus, our current study demonstrates that a subtle genetic variation (E160D) in BER genes (FEN1) may cause a functional deficiency in repairing base damage, such that individuals carrying the mutation or similar mutations are predisposed to chemical-induced cancer development.
    Oncogene 10/2010; 30(9):1072-81. DOI:10.1038/onc.2010.482 · 8.56 Impact Factor
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    ABSTRACT: Flap endonuclease 1 (FEN1), a structure-specific endo- and exonuclease, has multiple functions that determine essential biological processes, such as cell proliferation and cell death. As such, the enzyme must be precisely regulated to execute each of its functions with the right timing and in a specific subcellular location. Here we report that FEN1 is methylated at arginine residues, primarily at Arg192. The methylation suppresses FEN1 phosphorylation at Ser187. The methylated form, but not the phosphorylated form, of FEN1 strongly interacts with proliferating cell nuclear antigen (PCNA), ensuring the 'on' and 'off' timing of its reaction. Mutations of FEN1 disrupting arginine methylation and PCNA interaction result in unscheduled phosphorylation and a failure to localize to DNA replication or repair foci. This consequently leads to a defect in Okazaki fragment maturation, a delay in cell cycle progression, impairment of DNA repair and a high frequency of genome-wide mutations.
    Nature Chemical Biology 10/2010; 6(10):766-73. DOI:10.1038/nchembio.422 · 13.22 Impact Factor

Publication Stats

2k Citations
518.23 Total Impact Points

Institutions

  • 2002–2015
    • Beckman Research Institute
      Дуарте, California, United States
    • Kansas State University
      Манхэттен, Kansas, United States
  • 1998–2015
    • City of Hope National Medical Center
      • • Department of Radiation Biology
      • • Department of Molecular and Cellular Biology
      • • Department of Immunology
      • • Department of Molecular Medicine
      Дуарте, California, United States
  • 2012
    • The University of Sheffield
      • Department of Chemistry
      Sheffield, ENG, United Kingdom
  • 2005–2010
    • Zhejiang University
      • Institute of Nuclear Agricultural Sciences
      Hang-hsien, Zhejiang Sheng, China
  • 2004
    • Wright State University
      • Department of Biochemistry and Molecular Biology
      Dayton, Ohio, United States
    • The Scripps Research Institute
      • Skaggs Institute for Chemical Biology
      La Jolla, California, United States
  • 1995
    • Los Alamos National Laboratory
      • Life Sciences Division
      Лос-Аламос, California, United States