Cancer-associated SF3B1 mutation suppress DNA damage repair by disrupting circRNA biogenesis
Cancer-associated SF3B1 mutation leads to alternative splicing of hundreds of genes that affect cancer progression in multiple pathways. 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. Taken together, these data shed light on the mechanisms by which SF3B1 interferes with DNA damage repair, providing new perspectives for treating tumors with SF3B1 mutation. Overall design: In an effort to investigate whether SF3B1 mutation interferes with circRNA biogenesis, we performed RNA-seq of Hela and HEK293T cells with or without SF3B1 mutation to identify promising circRNA candidates.