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Structure of the helicase domain of DNA polymerase theta reveals a possible role in the microhomology- mediated end-joining pathway

DOI: 10.1016/j.str.2015.10.014 DOI Help
PMID: 26636256 PMID Help

Authors: Joseph A. Newman (Institute for Cell and Molecular Biosciences, Newcastle University) , Christopher D. O. Cooper (University of Oxford) , Hazel Aitkenhead (Beatson Institute for Cancer Research) , Opher Gileadi (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure , VOL 23 (12) , PAGES 2319 - 2330

State: Published (Approved)
Published: December 2015
Diamond Proposal Number(s): 8421 , 10619

Open Access Open Access

Abstract: DNA polymerase theta (Polθ) has been identified as a crucial alternative non-homologous end-joining factor in mammalian cells. Polθ is upregulated in a range of cancer cell types defective in homologous recombination, and knockdown has been shown to inhibit cell survival in a subset of these, making it an attractive target for cancer treatment. We present crystal structures of the helicase domain of human Polθ in the presence and absence of bound nucleotides, and a characterization of its DNA-binding and DNA-stimulated ATPase activities. Comparisons with related helicases from the Hel308 family identify several unique features. Polθ exists as a tetramer both in the crystals and in solution. We propose a model for DNA binding to the Polθ helicase domain in the context of the Polθ tetramer, which suggests a role for the helicase domain in strand annealing of DNA templates for subsequent processing by the polymerase domain.

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Medicine

Instruments: B21-High Throughput SAXS , I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Added On: 10/12/2015 14:48


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Scattering Macromolecular Crystallography (MX) Small Angle X-ray Scattering (SAXS)