title: ATM regulates a DNA damage response posttranscriptional RNA operon in lymphocytes.
abstract: Maintenance of genomic stability depends on the DNA damage response, a biologic barrier in early stages of cancer development. Failure of this response results in genomic instability and high predisposition toward lymphoma, as seen in patients with ataxia-telangiectasia mutated (ATM) dysfunction. ATM activates multiple cell-cycle checkpoints and DNA repair after DNA damage, but its influence on posttranscriptional gene expression has not been examined on a global level. We show that ionizing radiation modulates the dynamic association of the RNA-binding protein HuR with target mRNAs in an ATM-dependent manner, potentially coordinating the genotoxic response as an RNA operon. Pharmacologic ATM inhibition and use of ATM-null cells revealed a critical role for ATM in this process. Numerous mRNAs encoding cancer-related proteins were differentially associated with HuR depending on the functional state of ATM, in turn affecting expression of encoded proteins. The findings presented here reveal a previously unidentified role of ATM in controlling gene expression posttranscriptionally. Dysregulation of this DNA damage response RNA operon is probably relevant to lymphoma development in ataxia-telangiectasia persons. These novel RNA regulatory modules and genetic networks provide critical insight into the function of ATM in oncogenesis.
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Mazan-Mamczarz
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hagner
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bojie
authors.initials: B
authors.lastname: Dai
authors.forename: Elin
authors.initials: E
authors.lastname: Lehrmann
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Jack D
authors.initials: JD
authors.lastname: Keene
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.forename: Zhenqui
authors.initials: Z
authors.lastname: Liu
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Gartenhaus
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D008223:Lymphoma / Q000209:etiology; D050505:Mutant Proteins; D009876:Operon / Q000235:genetics*; D011485:Protein Binding / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D011839:Radiation, Ionizing; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000954:Antigens, Surface; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D050505:Mutant Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases