title: Human DNA polymerase θ grasps the primer terminus to mediate DNA repair.
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.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, USA.
authors.forename: Karl E
authors.initials: KE
authors.lastname: Zahn
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, USA.
authors.forename: April M
authors.initials: AM
authors.lastname: Averill
authors.affiliation: Diamond Light Source, Didcot, Oxfordshire, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Aller
authors.affiliation: Department of Epigenetics &Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, Texas, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wood
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Doublié
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000502:physiology*; D019281:Dimerization; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D000097462:DNA Polymerase theta
chemical_list: D004259:DNA-Directed DNA Polymerase; D000097462:DNA Polymerase theta