title: DNA-damage-induced nuclear export of precursor microRNAs is regulated by the ATM-AKT pathway.
abstract: Expression of microRNAs (miRNAs) involves transcription of miRNA genes and maturation of the primary transcripts. Recent studies have shown that posttranscriptional processing of primary and precursor miRNAs is induced after DNA damage through regulatory RNA-binding proteins in the Drosha and Dicer complexes, such as DDX5 and KSRP. However, little is known about the regulation of nuclear export of pre-miRNAs in the DNA-damage response, a critical step in miRNA maturation. Here, we show that nuclear export of pre-miRNAs is accelerated after DNA damage in an ATM-dependent manner. The ATM-activated AKT kinase phosphorylates Nup153, a key component of the nucleopore, leading to enhanced interaction between Nup153 and Exportin-5 (XPO5) and increased nuclear export of pre-miRNAs. These findings define an important role of DNA-damage signaling in miRNA transport and maturation.
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Guohui
authors.initials: G
authors.lastname: Wan
authors.forename: Xinna
authors.initials: X
authors.lastname: Zhang
authors.forename: Robert R
authors.initials: RR
authors.lastname: Langley
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Hu
authors.forename: Cecil
authors.initials: C
authors.lastname: Han
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Jones
authors.forename: Xiongbin
authors.initials: X
authors.lastname: Lu
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D045325:HCT116 Cells; D006801:Humans; D028884:Karyopherins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D028884:Karyopherins; D035683:MicroRNAs; C079377:NUP153 protein, human; D028861:Nuclear Pore Complex Proteins; C446511:XPO5 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051057:Proto-Oncogene Proteins c-akt