Epithelial cell transforming factor ECT2 is an important regulator of DNA double-strand break repair and genome stability.

Proteins containing breast cancer type 1 (BRCA1) C-terminal domains play crucial roles in response to and repair of DNA damage. Epithelial cell transforming factor (epithelial cell transforming sequence 2 [ECT2]) is a member of the BRCA1 C-terminal protein family, but it is not known if ECT2 directly contributes to DNA repair. In this study, we report that ECT2 is recruited to DNA lesions in a poly (ADP-ribose) polymerase 1-dependent manner. Using co-immunoprecipitation analysis, we showed that ECT2 physically associates with KU70-KU80 and BRCA1, proteins involved in nonhomologous end joining and homologous recombination, respectively. ECT2 deficiency impairs the recruitment of KU70 and BRCA1 to DNA damage sites, resulting in defective DNA double-strand break repair, an accumulation of damaged DNA, and hypersensitivity of cells to genotoxic insults. Interestingly, we demonstrated that ECT2 promotes DNA repair and genome integrity largely independently of its canonical guanine nucleotide exchange activity. Together, these results suggest that ECT2 is directly involved in DNA double-strand break repair and is an important genome caretaker.