title: Bidirectional coupling of splicing and ATM signaling in response to transcription-blocking DNA damage.
abstract: In response to DNA damage cells activate intricate protein networks to ensure genomic fidelity and tissue homeostasis. DNA damage response signaling pathways coordinate these networks and determine cellular fates, in part, by modulating RNA metabolism. Here we discuss a replication-independent pathway activated by transcription-blocking DNA lesions, which utilizes the ATM signaling kinase to regulate spliceosome function in a reciprocal manner. We present a model according to which, displacement of co-transcriptional spliceosomes from lesion-arrested RNA polymerases, culminates in R-loop formation and non-canonical ATM activation. ATM signals in a feed-forward fashion to further impede spliceosome organization and regulates UV-induced gene expression and alternative splicing genome-wide. This reciprocal coupling between ATM and the spliceosome highlights the importance of ATM signaling in the cellular response to transcription-blocking lesions and supports a key role of the splicing machinery in this process.
authors.affiliation: a Department of Genetics , Cancer Genomics Netherlands, Erasmus University Medical Center , Rotterdam , The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: Tresini
authors.affiliation: a Department of Genetics , Cancer Genomics Netherlands, Erasmus University Medical Center , Rotterdam , The Netherlands.
authors.forename: Jurgen A
authors.initials: JA
authors.lastname: Marteijn
authors.affiliation: a Department of Genetics , Cancer Genomics Netherlands, Erasmus University Medical Center , Rotterdam , The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Vermeulen
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D017381:Spliceosomes / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; Alternative splicing; DDR signaling; DNA damage; R-loops; UV irradiation; spliceosome; transcription