Transcription dynamics prevents RNA-mediated genomic instability through SRPK2-dependent DDX23 phosphorylation. Homo sapiens

Genomic instability is frequently caused by nucleic acids structures formed during transcription termed R-loops. Despite their harmful potential, mechanisms that sense, signal and suppress these structures remain elusive. Here we report that oscillations in transcription dynamics are a major sensor of R-loops. We show that pausing of RNA polymerase II (RNA Pol II) initiates a signaling cascade whereby the serine/arginine protein kinase 2 (SRPK2) phosphorylates the DDX23 helicase culminating in the suppression of R-loops. We show that in the absence of either SRPK2 or DDX23, accumulation of R-loops leads to massive genomic instability revealed by high levels of DNA double-strand breaks (DSBs). Importantly, we found DDX23 mutations in several cancers and detected homozygous deletions of the entire DDX23 locus in 10 (17%) adenoid cystic carcinoma samples. Our results unravel molecular details of a novel link between transcription dynamics and RNA-mediated genomic instability that may play important roles in cancer development. Overall design: To map the genomic occupancy of splicing factors SRPK1 and SRPK2, ChIP-seq was performed in MCF10A cells.