Cancer-associated SF3B1 mutation suppress DNA damage repair by disrupting circRNA biogenesis

It has been reported that SF3B1 mutation interrupt with DNA damage repair independent of the BRCA1/RAD51 pathway. Here, we report that SF3B1 mutation compromise DNA homologous recombination (HR) repair by disrupting circATP9B biogenesis to repair the later stages of Rad51 loading.

Mechanistically, circATP9B specifically binds to MYH9, and accelerate MYH9 protein degradation at the post-transcriptional level. circATP9B interferes with the motivity of DNA double-strand damage (DSB) sites by obstructing the assembly of nuclear actin and leads to persistent DSB sites in heterochromatin. It was further determined that the up-regulation of circATP9B enhanced the sensitivity of tumor cells to the PARP inhibitors, indicating that circATP9B interrupt with DNA damage repair.