Human HelQ and DNA polymerase δ interact to halt DNA synthesis and stimulate DNA single-strand annealing

DNA strand breaks can be repaired by base-pairing with unbroken homologous DNA, forming a template for new DNA synthesis that patches over the break site. In eukaryotes multiple DNA break repair pathways utilize DNA polymerase δ (Pol δ) to synthesise new DNA from the available 3’OH at the strand break. Here we show that DNA synthesis by human Pol δ is halted by the HelQ DNA repair protein directly targeting isolated Pol δ or Pol δ in complex with PCNA and RPA. The mechanism is independent of DNA binding by HelQ or Pol δ, maps to a region of HelQ that also modulates RPA, and requires multiple Pol δ subunits. Interaction of HelQ with the POLD3 subunit of Pol δ stimulated DNA single-strand annealing activity of HelQ. The data implicates HelQ in preventing genetic instability by restraining DNA synthesis in multiple DNA break repair pathways.