The internal region of CtIP functions as a regulator of DNA end resection

DNA double-strand breaks are repaired by end-joining or homologous recombination. A key-committing step of recombination is DNA end resection. In resection, phosphorylated CtIP first promotes the endonuclease of the MRE11-RAD50-NBS1 (MRN) complex. Subsequently, CtIP also stimulates the BLM-DNA2 helicase-nuclease, coordinating thus both short and long-range resection. The structure of CtIP differs from its orthologues in yeast, as it contains a large internal region. Here we conducted a domain analysis of the internal region of CtIP to define its function in DNA end resection. We found that residues 350-600 were entirely dispensable for resection in vitro. A mutant lacking these residues was unexpectedly more efficient than full-length CtIP in DNA end resection and homologous recombination in vivo, and consequently conferred resistance to lesions induced by the topoisomerase poison camptothecin, which require high MRN-CtIP-dependent resection activity for repair. This suggested that the ...