Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP

DNA double-strand break repair by homologous recombination entails the resection of DNA ends to reveal ssDNA tails, which are used to invade a homologous DNA template. CtIP and its yeast ortholog Sae2 regulate the nuclease activity of MRE11 in the initial stage of resection. Deletion of CtIP in the mouse or SAE2 in yeast engenders a more severe phenotype than MRE11 nuclease inactivation, indicative of a broader role of CtIP/Sae2. Here, we provide biochemical evidence that CtIP promotes long-range resection via the BLM-DNA2 pathway. Specifically, CtIP interacts with BLM and enhances its helicase activity, and it enhances DNA cleavage by DNA2. Thus, CtIP influences multiple aspects of end resection beyond MRE11 regulation. [Display omitted] •CtIP enhances long-range resection by BLM-DNA2-RPA•CtIP interacts with and stimulates the activity of the BLM helicase•CtIP upregulates the endonuclease activity of DNA2•CtIP tetramerization is important for stimulation of long-range resection Biochemical analysis by Daley et al. shows that CtIP not only functions as a cofactor for the MRN complex but also stimulates long-range resection by BLM-DNA2-RPA. CtIP interacts with BLM and enhances its helicase activity, and it upregulates the DNA flap cleavage activity of DNA2.