Structural basis for allosteric regulation of Human Topoisomerase IIα

Area of Science:

• Molecular biology
• Structural biology
• Biochemistry

Background:

• Human topoisomerase IIα (Top2α) is essential for DNA topology regulation and chromosome organization.
• Top2α is a key target for anticancer drugs, forming complexes with DNA.
• Limited structural data exists for the full Top2α enzyme, hindering understanding of its allosteric regulation and C-terminal domain (CTD) function.

Purpose of the Study:

• To determine the cryo-electron microscopy (cryo-EM) structures of the entire human Topo IIα nucleoprotein complex.
• To elucidate the molecular mechanisms underlying allosteric regulation between Top2α domains.
• To investigate the role of the C-terminal domain (CTD) in Top2α activity.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to solve structures of the human Topo IIα nucleoprotein complex.
• Structures were obtained at subnanometer resolutions (3.6–7.4 Å).
• Analysis focused on different conformational states of the enzyme.

Main Results:

• Novel cryo-EM structures of the complete human Topo IIα nucleoprotein complex in various conformations were obtained.
• The structures reveal molecular details of allosteric communication between the ATPase and DNA binding/cleavage domains.
• A linker connecting the DNA-binding/cleavage domain to the CTD was identified, highlighting its role in modulating enzyme activity.

Conclusions:

• The study provides unprecedented structural insights into the full human Topo IIα enzyme.
• Understanding Top2α allosteric mechanisms and CTD function opens new avenues for cancer therapy development.
• The findings facilitate further research into Top2α regulation, including post-translational modifications.