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Nat Struct Mol Biol. 2015 Apr;22(4):304-11. doi: 10.1038/nsmb.2993. Epub 2015 Mar 16.

Human DNA polymerase θ grasps the primer terminus to mediate DNA repair.

Author information

1
Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, USA.
2
Diamond Light Source, Didcot, Oxfordshire, UK.
3
Department of Epigenetics &Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.

Abstract

DNA polymerase θ protects against genomic instability via an alternative end-joining repair pathway for DNA double-strand breaks. Polymerase θ is overexpressed in breast, lung and oral cancers, and reduction of its activity in mammalian cells increases sensitivity to double-strand break-inducing agents, including ionizing radiation. Reported here are crystal structures of the C-terminal polymerase domain from human polymerase θ, illustrating two potential modes of dimerization. One structure depicts insertion of ddATP opposite an abasic-site analog during translesion DNA synthesis. The second structure describes a cognate ddGTP complex. Polymerase θ uses a specialized thumb subdomain to establish unique upstream contacts to the primer DNA strand, including an interaction with the 3'-terminal phosphate from one of five distinctive insertion loops. These observations demonstrate how polymerase θ grasps the primer to bypass DNA lesions or extend poorly annealed DNA termini to mediate end-joining.

PMID:
25775267
PMCID:
PMC4385486
DOI:
10.1038/nsmb.2993
[Indexed for MEDLINE]
Free PMC Article

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