Structure of human DNA pol theta - a role in breast cancer
Sylvie Doublie group (University of Vermont)
The group of Sylvie Doublie at the University of Vermont and
collaborators determined the first crystal structure of human DNA polymerase
theta (pol theta) complexed to nucleotides and lesion-containing DNA. The
human POLQ gene encodes pol theta, a specialized family-A DNA polymerase
over-expressed in breast and ovarian cancers. Pol theta participates in an
alternative end-joining pathway to repair DNA double-strand breaks, thus
contributing to genome stability. This work uncovers the basis of pol theta
specialization, demonstrating how conserved arginine and lysine amino acids
of the thumb subdomain enhance the protein's hold on the DNA phosphate
backbone to mediate end-joining. One such arginine (Arg2254) is uniquely
poised to stabilize the primer terminus and is absolutely required for
efficient bypass of non-templating DNA lesions. The structures also
demonstrate potential for transient higher-order pol theta complexes, which
could provide a novel route for pharmacological inhibition in future cancer
therapies.
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Figure: Two molecules of Human DNA
pol theta bind lesion containing double-stranded DNA. |
Citation: Zahn KE, Averill AM, Aller P, Wood RD, Doublie
S. Human DNA polymerase θ grasps the primer terminus to mediate DNA
repair. Nat Struct Mol Biol. 2015 Apr;22(4):304-11.
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