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dc.contributor.authorRamachandran, S
dc.contributor.authorTran, D
dc.contributor.authorKlebba-Faerber, S
dc.contributor.authorKardinal, C
dc.contributor.authorWhetton, Anthony D
dc.contributor.authorTamura, T
dc.date.accessioned2012-03-01T13:43:17Z
dc.date.available2012-03-01T13:43:17Z
dc.date.issued2011-11
dc.identifier.citationAn ataxia-telangiectasia-mutated (ATM) kinase mediated response to DNA damage down-regulates the mRNA-binding potential of THOC5. 2011, 17 (11):1957-66 RNAen
dc.identifier.issn1469-9001
dc.identifier.pmid21937706
dc.identifier.doi10.1261/rna.2820911
dc.identifier.urihttp://hdl.handle.net/10541/213750
dc.description.abstractIn response to DNA damage, transcription is blocked by inhibition of RNA polymerase II activity. The regulation of a preexisting pool of mRNAs, therefore, plays a key role in DNA repair, cell cycle arrest, or inhibition of differentiation. THOC5 is a member of the THO complex and plays a role in the export of a subset of mRNA, which plays an important role in hematopoiesis and maintaining primitive cells. Since three serine residues in the PEST domain of THOC5 have been shown to be directly phosphorylated by ataxia-telangiectasia-mutated (ATM) kinase, we examined the THOC5-dependent mRNA export under DNA damage. We show here that DNA damage drastically decreased the cytoplasmic pool of a set of THOC5-dependent mRNAs and impaired the THOC5/mRNA complex formation. The mRNP complex formed with nonphosphorylation mutant (S307/312/314A) THOC5, but not with a C-terminal deletion mutant after DNA damage, suggesting that the C-terminal domain of THOC5, but not its phosphorylation in the PEST domain, is necessary for the regulation of the mRNA-binding potency of THOC5. The cytoplasmic THOC5-dependent mRNAs were recovered by treatment with ATM kinase-specific or p53-specific siRNA, as well as by treatment with ATM kinase inhibitor, KU55933, under DNA damage conditions, suggesting that the ATM-kinase-p53 pathway is involved in this response to the DNA damage. Furthermore, the treatment with KU55933 blocked DNA damage-induced THOC5mRNP complex dissociation, indicating that activation of ATM kinase suppresses the ability of THOC5 to bind to its target mRNAs.
dc.language.isoenen
dc.subject.meshAnimals
dc.subject.meshCell Cycle Proteins
dc.subject.meshCells, Cultured
dc.subject.meshDNA Damage
dc.subject.meshDNA-Binding Proteins
dc.subject.meshDown-Regulation
dc.subject.meshMice
dc.subject.meshMutation
dc.subject.meshNuclear Proteins
dc.subject.meshProtein-Serine-Threonine Kinases
dc.subject.meshRNA, Messenger
dc.subject.meshRNA-Binding Proteins
dc.subject.meshTumor Suppressor Proteins
dc.titleAn ataxia-telangiectasia-mutated (ATM) kinase mediated response to DNA damage down-regulates the mRNA-binding potential of THOC5.en
dc.typeArticleen
dc.contributor.departmentInstitut für Biochemie, OE4310, Medizinische Hochschule Hannover, D-30623 Hannover, Germany.en
dc.identifier.journalRNAen
html.description.abstractIn response to DNA damage, transcription is blocked by inhibition of RNA polymerase II activity. The regulation of a preexisting pool of mRNAs, therefore, plays a key role in DNA repair, cell cycle arrest, or inhibition of differentiation. THOC5 is a member of the THO complex and plays a role in the export of a subset of mRNA, which plays an important role in hematopoiesis and maintaining primitive cells. Since three serine residues in the PEST domain of THOC5 have been shown to be directly phosphorylated by ataxia-telangiectasia-mutated (ATM) kinase, we examined the THOC5-dependent mRNA export under DNA damage. We show here that DNA damage drastically decreased the cytoplasmic pool of a set of THOC5-dependent mRNAs and impaired the THOC5/mRNA complex formation. The mRNP complex formed with nonphosphorylation mutant (S307/312/314A) THOC5, but not with a C-terminal deletion mutant after DNA damage, suggesting that the C-terminal domain of THOC5, but not its phosphorylation in the PEST domain, is necessary for the regulation of the mRNA-binding potency of THOC5. The cytoplasmic THOC5-dependent mRNAs were recovered by treatment with ATM kinase-specific or p53-specific siRNA, as well as by treatment with ATM kinase inhibitor, KU55933, under DNA damage conditions, suggesting that the ATM-kinase-p53 pathway is involved in this response to the DNA damage. Furthermore, the treatment with KU55933 blocked DNA damage-induced THOC5mRNP complex dissociation, indicating that activation of ATM kinase suppresses the ability of THOC5 to bind to its target mRNAs.


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