ssDNA hand-off from RPA to Polθ drives microhomology-mediated end-joining

RPA is essential for DNA polymerase theta-mediated end joining (TMEJ) in mitosis, where it activates Polθ by handing off resected ssDNA for microhomology search.

• Why it matters: RPA was previously thought to inhibit TMEJ by blocking microhomology search, leaving the true role of RPA in BRCA-deficient mitotic repair unclear.
• What they did: Using structural, biochemical, and genetic analyses, the study models Polθ binding directly to RPA at resected DNA ends and competing with RPA to release ssDNA into Polθ’s helicase domain.
• The result: The proposed Polθ dimer threading of two DNA ends initiates microhomology search, establishing a mechanism for how proteins harness RPA to access ssDNA for genome maintenance.