Templated Insertions - DNA Repair Gets Acrobatic.

Deletions associated with repair of DNA double strand breaks is a source of genetic alternation and a recognized source of disease-causing mutagenesis. Theta-mediated end joining (TMEJ) is a DNA repair mechanism which guarantees deletions by its employment of microhomology alignment to facilitate end joining. A lesser-characterized templated insertion ability of this pathway, on the other hand, is associated with both deletion and insertion. This mechanism is characterized by a first round of polymerase θ-mediated synthesis which does not result in successful repair, requiring subsequent rounds of polymerase engagement. Here we focus on the mechanisms by which polymerase θ introduces these insertions - direct, inverse, and a new class which we've termed strand switching. We observe this new class of templated insertions at multiple loci and across multiple species, often at a comparable frequency to those previously characterized. Templated insertion mutations are often enriched in cancer genomes and repeat expansion disorders. This repair mechanism thus contributes to disease-associated mutagenesis, and may plausibly even promote disease. Characterization of the types of polymerase θ-dependent insertions can provide new insight into these diseases and clinical promise for treatment. This article is protected by copyright. All rights reserved.