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Structure of the Helicase Domain of DNA Polymerase Theta Reveals a Possible Role in the Microhomology-Mediated End-Joining Pathway.

ABSTRACT: DNA polymerase theta (Pol?) has been identified as a crucial alternative non-homologous end-joining factor in mammalian cells. Pol? 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 Pol? 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. Pol? exists as a tetramer both in the crystals and in solution. We propose a model for DNA binding to the Pol? helicase domain in the context of the Pol? tetramer, which suggests a role for the helicase domain in strand annealing of DNA templates for subsequent processing by the polymerase domain.

SUBMITTER: Newman JA 

PROVIDER: S-EPMC4671958 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Structure of the Helicase Domain of DNA Polymerase Theta Reveals a Possible Role in the Microhomology-Mediated End-Joining Pathway.

Newman Joseph A JA   Cooper Christopher D O CDO   Aitkenhead Hazel H   Gileadi Opher O  

Structure (London, England : 1993) 20151201 12

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-bi  ...[more]

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