The BRCA1 gene is involved in repair of DNA breaks, and is frequently mutated in breast and ovarian cancer. Van de Kooij and colleagues carefully analyzed survival of cell-lines genetically engineered to have either a wild-type or a mutant BRCA1 gene. They found that genetic inactivation of EXO1 severely impaired survival of BRCA1-mutant cells, but not of BRCA1 wild-type cells.
EXO1 is an enzyme that turns double-stranded DNA into single-strand DNA during repair of DNA breaks. By detailed molecular and genetic analysis of DNA break repair and genome stability, van de Kooij and colleagues show that DNA break repair is hampered but still active in absence of BRCA1 or EXO1 alone, because the two genes can partially compensate for each others loss. However, inactivation of both BRCA1 and EXO1 substantially impairs DNA break repair resulting in toxic chromosomal instability. Consistent with these results in cell lines, the authors find genetic evidence in human tumor sequencing data to support that BRCA1-mutated tumors are strongly dependent on DNA repair via EXO1.
These findings imply that EXO1 might be targeted therapeutically to kill BRCA1-mutant tumor cells. Future research, spearheaded at the Leiden University Medical Center, will therefore focus on the development of specific small molecule inhibitors of the enzymatic activity of EXO1. Subsequently, these inhibitors, as well as genetic techniques, will be used in mouse studies to further the preclinical investigation on EXO1 as a therapeutic target.
