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

ABSTRACT: DNA polymerase ? protects against genomic instability via an alternative end-joining repair pathway for DNA double-strand breaks. Polymerase ? 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 ?, 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 ? 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 ? grasps the primer to bypass DNA lesions or extend poorly annealed DNA termini to mediate end-joining.

SUBMITTER: Zahn KE 

PROVIDER: S-EPMC4385486 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature