4.7 Article

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

Journal

NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 22, Issue 4, Pages 304-U51

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2993

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Funding

  1. US National Institutes of Health [R01 CA052040, CA097175]
  2. Cancer Prevention and Research Institute of Texas [RP130297]
  3. Grady F. Saunders PhD. Distinguished Research Professorship
  4. US National Cancer Institute [ACB-12002]
  5. US National Institute of General Medical Sciences [AGM-12006]
  6. US DOE Office of Science by Argonne National Laboratory [DE-AC02-06CH11357]

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

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