Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Loss of the Werner syndrome protein (WRN) helicase is a vulnerability in microsatellite instable (MSI) cancers.
• WRN is crucial for maintaining genome integrity and cell viability in MSI cancer cells.
• WRN is a promising drug target for MSI cancer therapy.

Purpose of the Study:

• To elucidate the structural basis of WRN helicase function in MSI cancer cells.
• To provide insights for structure-based drug development targeting WRN.

Main Methods:

• X-ray crystallography of the WRN helicase core (residues 517-1,093) at 2.2-Å resolution.
• Biochemical assays to demonstrate the requirement of ATP binding and hydrolysis.
• DNA binding modeling and Nuclear Magnetic Resonance (NMR) analysis.

Main Results:

• Reported the crystal structure of the WRN helicase core, revealing an atypical nucleotide binding mode and unique structural features.
• Identified an additional β-hairpin and an unusual helical hairpin in the WRN helicase structure.
• NMR analysis indicated a weak interaction between the HRDC domain and the helicase core.

Conclusions:

• The unique structural features of WRN may be involved in binding alternative DNA structures.
• The findings facilitate structure-based development of WRN helicase inhibitors for MSI cancer treatment.