Browsing by Author "Chen, Luan"

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    Dynamics of Ewing's sarcoma initiation and progression: Mathematical and statistical studies on stochastic multistage bone cancer model
    (2014-04-16) Chen, Luan
    wing’s sarcoma(ES) is a rare children bone cancer, which is also known as sarcoma keratin positive. It belongs to a tumor family that consistently related to chromosomal translocation and functional fusion of the EWS gene. Most of its pathognomonic translocation has been found to include the ews gene on chromosome 22 and an ets-type gene(most commonly fli1 gene) on chromosome 11.We used mathematical approach to study and describe the process of Ewing’s sarcoma initiation and progression. To model the carcinogenesis process of ES, we assumed that ES is initiated from the small number of mutated MSC in the tissue compartments of bone marrow with a homogeneous MSC population in the given time. We also incorporated the latest biological research discovery that only a small number of MSCs are at risk of the chromosomal translocation of ews gene, which is responsible for homeostatic regulation of MSCs. Using Kolmogorov forward equations, the ES formation dynamics are simulated by a low-dimensional stochastic process. We expect to assess the impact of variation in bone growth among individuals on ES risk using this model.
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    Structural asymmetry in the Thermus thermophilus RuvC dimer suggests a basis for sequential strand cleavages during Holliday junction resolution
    (2012-04-18) Chen, Luan
    Holliday junction (HJ) resolvases are structure-specific endonucleases that cleave four-way DNA junctions (Holliday junctions) generated during DNA recombination and repair. Bacterial RuvC, a prototype of HJ resolvase, functions as a homodimer and nicks DNA strands precisely across the junction point. To gain insights into the mechanisms underlying specific recognition of HJ DNA and symmetrical strand cleavages by RuvC, we performed crystallographic and biochemical analyses of RuvC from Thermus thermophilus (T.th. RuvC). The crystal structure of T.th. RuvC shows an overall protein fold similar to that of Escherichia coli RuvC, but T.th. RuvC has a more tightly associated dimer interface possibly reflecting its thermostability. The binding mode of a HJ-DNA substrate can be inferred from the shape/charge complementarity between the RuvC dimer and HJ-DNA, as well as positions of sulfate ions bound on the protein surface. Unexpectedly, the crystal structure of T.th. RuvC homodimer refined at 1.28Å resolution shows distinct asymmetry near the dimer interface, in the region harboring catalytically important aromatic residues. The observation suggests that the T.th. RuvC homodimer interconverts between two asymmetric conformations, with alternating subunits switched on for DNA strand cleavage. This model provides a structural basis for the “nick-counter-nick” mechanism in HJ resolution, a mode of HJ processing shared by prokaryotic and eukaryotic HJ resolvases.