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

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 in this paper 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. Finally, these observations demonstrate how polymerase θ grasps the primer to bypass DNA lesions or extend poorly annealed DNA termini to mediate end-joining.
Authors:
 [1] ;  [1] ;  [2] ;  [3] ;  [1]
  1. Univ. of Vermont, Burlington, VT (United States). Dept. of Microbiology and Molecular Genetics
  2. Diamond Light Source, Didcot (United Kingdom)
  3. Univ. of Texas MD Anderson Cancer Center, Smithville, TX (United States). Dept. of Epigenetics & Molecular Carcinogenesis
Publication Date:
OSTI Identifier:
1197030
Grant/Contract Number:
AC02-06CH11357; R01 CA052040; CA097175; RP130297; ACB-12002; AGM-12006
Type:
Accepted Manuscript
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 22; Journal Issue: 4; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Research Org:
Univ. of Vermont, Burlington, VT (United States)
Sponsoring Org:
USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); Cancer Prevention and Research Inst. of Texas (United States)
Contributing Orgs:
Diamond Light Source, Didcot (United Kingdom); Univ. of Texas MD Anderson Cancer Center, Smithville, TX (United States)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Cancer; Double-strand DNA breaks; Translesion synthesis; X-ray crystallography