Abstract
Summary 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.
| Original language | English |
|---|---|
| Pages (from-to) | 2319-2330 |
| Number of pages | 12 |
| Journal | Structure |
| Volume | 23 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 1 Dec 2015 |
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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.; Cooper, Christopher D O; Aitkenhead, Hazel; Gileadi, Opher.
In: Structure, Vol. 23, No. 12, 01.12.2015, p. 2319-2330.Research output: Contribution to journal › Article
TY - JOUR
T1 - Structure of the Helicase Domain of DNA Polymerase Theta Reveals a Possible Role in the Microhomology-Mediated End-Joining Pathway
AU - Newman, Joseph A.
AU - Cooper, Christopher D O
AU - Aitkenhead, Hazel
AU - Gileadi, Opher
PY - 2015/12/1
Y1 - 2015/12/1
N2 - Summary 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.
AB - Summary 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.
UR - http://www.scopus.com/inward/record.url?scp=84949215325&partnerID=8YFLogxK
UR - http://eprints.hud.ac.uk/id/eprint/26632/
U2 - 10.1016/j.str.2015.10.014
DO - 10.1016/j.str.2015.10.014
M3 - Article
VL - 23
SP - 2319
EP - 2330
JO - Structure with Folding & design
JF - Structure with Folding & design
SN - 0969-2126
IS - 12
ER -