title: Effects of the Bowen-Conradi syndrome mutation in EMG1 on its nuclear import, stability and nucleolar recruitment.
abstract: Bowen-Conradi syndrome (BCS) is a severe genetic disorder that is characterised by various developmental abnormalities, bone marrow failure and early infant death. This disease is caused by a single mutation leading to the aspartate 86 to glycine (D86G) exchange in the essential nucleolar RNA methyltransferase EMG1. EMG1 is required for the synthesis of the small ribosomal subunit and is involved in modification of the 18S ribosomal RNA. Here, we identify the pre-ribosomal factors NOP14, NOC4L and UTP14A as members of a nucleolar subcomplex that contains EMG1 and is required for its recruitment to nucleoli. The BCS mutation in EMG1 leads to reduced nucleolar localisation, accumulation of EMG1D86G in nuclear foci and its proteasome-dependent degradation. We further show that EMG1 can be imported into the nucleus by the importins (Imp) Impα/β or Impβ/7. Interestingly, in addition to its role in nuclear import, binding of the Impβ/7 heterodimer can prevent unspecific aggregation of both EMG1 and EMG1D86G on RNAs in vitro, indicating that the importins act as chaperones by binding to basic regions of the RNA methyltransferase. Our findings further indicate that in BCS, nuclear disassembly of the import complex and release of EMG1D86G lead to its nuclear aggregation and degradation, resulting in the reduced nucleolar recruitment of the RNA methyltransferase and defects in the biogenesis of the small ribosomal subunit.
authors: Institute for Molecular Biology, Georg-August University, Göttingen, Germany.
authors: Ahmed S
authors: AS
authors: Warda
authors: Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors: Bernard
authors: B
authors: Freytag
authors: Institute for Molecular Biology, Georg-August University, Göttingen, Germany.
authors: Sara
authors: S
authors: Haag
authors: Institute for Molecular Biology, Georg-August University, Göttingen, Germany.
authors: Katherine E
authors: KE
authors: Sloan
authors: Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors: Dirk
authors: D
authors: Görlich
authors: Institute for Molecular Biology, Georg-August University, Göttingen, Germany.|Göttingen Center for Molecular Biosciences, Georg-August-University, Göttingen, Germany.
authors: Markus T
authors: MT
authors: Bohnsack
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics*; D002466:Cell Nucleolus / Q000235:genetics / Q000378:metabolism; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D008780:Methyltransferases / Q000235:genetics*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011596:Psychomotor Disorders / Q000235:genetics* / Q000473:pathology; D012337:RNA, Ribosomal, 18S / Q000235:genetics; D028961:beta Karyopherins / Q000235:genetics / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; C115775:NOP14 protein, human; D009687:Nuclear Proteins; D012337:RNA, Ribosomal, 18S; D028961:beta Karyopherins; C549212:EMG1 protein, human; D008780:Methyltransferases