Templated insertions—DNA repair gets acrobatic

Abstract

AbstractDeletions associated with the repair of DNA double‐strand breaks is a source of genetic alternation and a recognized source of disease‐causing mutagenesis. Theta‐mediated end joining is a DNA repair mechanism, which guarantees deletions by its employment of microhomology (MH) 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 at least one round of polymerase θ‐mediated synthesis, which does not result in successful repair, followed by a subsequent round of polymerase engagement and synthesis that does lead to repair. Here we focus on the mechanisms by which polymerase θ introduces these insertions—direct, inverse, and a new class which we have 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.