Chromosome breaks are a serious threat to the stability of the genome, and when left unrepaired can cause cell death. DNA Polymerase Theta (Pol θ) is central to a chromosome break repair pathway that is rarely used in normal cells but is hyperactive in certain cancers. Because some breast and ovarian tumors rely on Pol θ for survival, it is a promising therapeutic target against these tumors. Pol θ has to find short, complementary sequences in the DNA. In this paper, we show how it scans the DNA to find them in a way that minimizes the loss of DNA. If these complementary sequences are not present, Pol θ creates them, generating new DNA sequences that we call templated insertions. Templated insertions are a very characteristic type of mutation, that we demonstrated is common in breast tumors with mutations in BRCA1 and BRCA2, as well as tumors that overexpress Pol θ. We propose that looking for templated insertions in the genomes of breast and ovarian tumors is a way to assess whether this protein is active, which would make the tumor sensitive to a drug that targets Pol θ.
Mechanistic basis for microhomology identification and genome scarring by polymerase theta link to publication.