Genomic instability is frequently caused by nucleic acid structures termed R-loops that are formed during transcription. 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 (ACC) samples. Our results unravel molecular details of a link between transcription dynamics and RNA-mediated genomic instability that may play important roles in cancer development.
Sridhara, S. C., Carvalho, S., Grosso, A. R., Gallego-Paez, L. M., Carmo-Fonseca, M., & de Almeida, S. F. (2017). Transcription Dynamics Prevent RNA-Mediated Genomic Instability through SRPK2-Dependent DDX23 Phosphorylation. Cell Reports, 18(2), 334–343. https://doi.org/10.1016/j.celrep.2016.12.050