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.