A direct RPA-Polθ interaction licenses theta-mediated end joining

Disrupting the RPA2–polymerase theta (Polθ) interface abolishes cellular theta-mediated end joining (TMEJ) while leaving homologous recombination and viability intact.

• Why it matters: It remains unclear how resected DNA ends are routed to specific repair pathways, and RPA was thought to block TMEJ rather than enable it.
• What they did: Using MUSIC-MAP to link endogenous sequence variants to repair outcomes, the study mapped a functional interface between RPA2 and Polθ and tested interface-disrupting and complementary charge-reversal mutations.
• The result: Polθ surface mutations impair TMEJ, while reciprocal charge-reversal mutations in RPA2 and Polθ restore it, supporting a direct physical interaction and a model where RPA-coated ssDNA termini expose the Polθ-binding surface.