Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting
An artificial lethal relationship exists between disruption of polymerase theta (Pol?), and lack of either 53BP1 or homologous recombination (HR) proteins, including BRCA1 however, the mechanistic foundation of these observations are unclear. Ideas reveal two distinct mechanisms of Pol? synthetic lethality, identifying dual influences of just one) whether Pol? sheds or inhibited, and a pair of) the actual susceptible genotype. First of all, we discover the sensitivity of BRCA1/2- and 53BP1-deficient cells to Pol? loss, and 53BP1-deficient cells to Pol? inhibition (ART558) requires RAD52, and appropriate decrease in RAD52 can improve these phenotypes. We reveal that even without the Pol?, RAD52 accumulations suppress ssDNA gap-filling out G2/M and encourage MRE11 nuclease accumulation. In comparison, the survival of BRCA1-deficient cells given Pol? inhibitor aren’t restored by RAD52 suppression, and ssDNA gap-filling is avoided through the chemically inhibited polymerase itself. These data define yet another role for Pol?, reveal the mechanism underlying synthetic lethality between 53BP1, BRCA1/2 and Pol? loss, and indicate genotype-dependent Pol? inhibitor mechanisms.