title: Transcription Dynamics Prevent RNA-Mediated Genomic Instability through SRPK2-Dependent DDX23 Phosphorylation.
abstract: 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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1600-276 Lisboa, Portugal.
authors.forename: Sreerama Chaitanya
authors.initials: SC
authors.lastname: Sridhara
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1600-276 Lisboa, Portugal.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Carvalho
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1600-276 Lisboa, Portugal.
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Grosso
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1600-276 Lisboa, Portugal.
authors.forename: Lina Marcela
authors.initials: LM
authors.lastname: Gallego-Paez
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1600-276 Lisboa, Portugal.
authors.forename: Maria
authors.initials: M
authors.lastname: Carmo-Fonseca
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1600-276 Lisboa, Portugal. Electronic address: sergioalmeida@fm.ul.pt.
authors.forename: Sérgio Fernandes
authors.initials: SF
authors.lastname: de Almeida
mesh_terms: D003528:Carcinoma, Adenoid Cystic / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D004249:DNA Damage; D042822:Genomic Instability; D006801:Humans; D009690:Nucleic Acid Conformation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D020871:RNA Stability / Q000235:genetics*; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000378:metabolism; D017381:Spliceosomes / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D017415:Ribonucleoprotein, U5 Small Nuclear; D017346:Protein Serine-Threonine Kinases; C110522:SRPK2 protein, human; C498290:DDX23 protein, human; D012319:RNA Polymerase II; D053487:DEAD-box RNA Helicases
keywords: DDX23; R-loops; RNA polymerase II; SRPK2; genomic instability; transcription dynamics