Editor’s summary
DNA breakage can cause chromosome rearrangements, which are a hallmark of cancer. DNA break repair can occur by DNA joining or homologous recombination, with the latter being dependent on the gene BRCA1, mutations of which cause familial breast and ovarian cancers. BRCA1 promotes DNA resection, a process that creates a crucial DNA intermediate needed for successful repair. Rogers et al. uncovered a multilayered mechanism by which the CTC1-STN1-TEN1 (CST) complex, a known DNA-joining factor, negatively regulates DNA resection. Importantly, they showed that BRCA1 alleviates the CST-mediated DNA resection blockade. These findings have implications for understanding drug resistance arising in tumors deficient in BRCA1. —Di Jiang
Abstract
Antagonistic activities of the 53BP1 axis and the tumor suppressor BRCA1-BARD1 determine whether DNA double-strand breaks (DSBs) are repaired by end joining or homologous recombination. We show that the CTC1-STN1-TEN1 (CST) complex, a central 53BP1 axis component, suppresses DNA end resection by EXO1 and the BLM-DNA2 helicase-nuclease complex but acts by distinct mechanisms in restricting these entities. Whereas BRCA1-BARD1 alleviates the CST-imposed EXO1 blockade, it has little effect on BLM-DNA2 restriction. CST mutants impaired for DNA binding or BLM–EXO1 interaction exhibit a hyper-resection phenotype and render BRCA1-deficient cells resistant to poly(ADP–ribose) polymerase (PARP) inhibitors. Our findings mechanistically define the crucial role of CST in DNA DSB repair pathway choice and have implications for understanding cancer therapy resistance stemming from dysfunction of the 53BP1 axis.