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Mus81-Eme1-flap DNA 복합체의 구조와 기능에 관한 연구

Mus81-Eme1-flap DNA 복합체의 구조와 기능에 관한 연구
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The Mus81-Eme1 complex is a structure-selective endonuclease with a critical role in the resolution of recombination intermediates during DNA repair after interstrand crosslinks, replication fork collapse or double strand breaks. Although we analysis the Mus81-Eme1 complex structure and ApeXPF-DNA complex structure, we don’t know recognition and cleavage of substrate. To explain the molecular basis of nicked Holliday junction (nHJ), 3’ flap substrates recognition and cleavage mechanism by Mus81-Eme1, we determined crystal structures of human Mus81-Eme1 bound to various flap DNA substrates, studied fluorescence resonance energy transfer (FRET), and mutational results. Mus81-Eme1 undergoes gross substrate-induced conformational changes that reveal three key features
(i) a hydrophobic wedge of Mus81 that separates pre- and post-nick duplex DNA and (ii) a “5’ end binding pocket” that grasps the 5’ nicked end of post-nick DNA. (iii) Binding to DNA induces a disorder-to-order transition of Eme1 linker followed by rotation of the helix-hairpin-helix domain, which unmasks hydrophobic wedge, active sites and the 5’ end binding pocket to facilitate DNA kinking and junction recognition. These features are crucial for comprehensive protein-DNA interaction, sharp bending of the 3’ flap DNA substrate, and incision strand placement at the active site. Interestingly Mus81-Eme1 unexpectedly shares several common features with members of the 5’ flap nuclease family (FEN1, Exo1), the combined structural, biochemical and biophysical analyses explain why Mus81-Eme1 preferentially cleaves 3’ flap DNA substrates with 5’-nicked ends.
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