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. Author manuscript; available in PMC: 2017 Apr 9.
Published in final edited form as: Nat Rev Mol Cell Biol. 2016 May 11;17(6):364–378. doi: 10.1038/nrm.2016.43

Figure 5. The mechanism by which DNA polymerase θ (Pol θ) promotes alternative non-homologous end joining (alt-NHEJ).

Figure 5

Sequence analysis of shelterin-free telomeres in Ku-deficient cells identified random nucleotide insertions at telomere fusion junctions. Subsequent genetic studies identified Pol θ as a key alt-NHEJ factor that promotes the joining of dysfunctional telomeres. Following double-strand break (DSB) formation or telomere uncapping, DNA ends are resected to create short 3′ overhangs. On the basis of in vitro experiments, genetic studies and sequence analysis of fusion junctions, Pol θ seems to be capable of extending the 3′ single-stranded DNA (ssDNA) using a combination of template-dependent as well as template-independent activities, the latter potentially mediated through a snap-back intermediate. The incorporation of random nucleotides as sites of breaks is predicted to increase the level of microhomology, thereby promoting the synapsis of opposite ends of a DSB. Annealed intermediates are then subject to fill-in synthesis by Pol θ, a step that would stabilize the duplexed DNA. Ultimately, the DNA is joined by DNA ligase 3.