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.
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http://dx.doi.org/10.1093/hmg/ddw351 | DOI Listing |
Front Genet
January 2025
Department of Gynecology, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, China.
Background: Endometriosis, a prevalent chronic gynecological condition, is frequently associated with infertility and pelvic pain. Despite numerous studies indicating a correlation between epigenetic regulation and endometriosis, its precise genetic etiology remains elusive. Methyltransferase-like 14 (METTL14), a crucial component of the N6-methyladenosine (mA) RNA methyltransferase complex and an RNA binding scaffold, is known to play a pivotal role in various human diseases.
View Article and Find Full Text PDFUnlabelled: The activity of DNA adenine methyltransferase (Dam) and DNA cytosine methyltransferase (Dcm) together account for nearly all methylated nucleotides in the K-12 MG1655 genome. Previous studies have shown that perturbation of DNA methylation alters global gene expression, but it is unclear whether the methylation state of Dam or Dcm target sites regulates local transcription. In recent genome-wide experiments, we observed an underrepresentation of Dam sites in transcriptionally silent extended protein occupancy domains (EPODs), prompting us to hypothesize that EPOD formation is caused partially by low Dam site density.
View Article and Find Full Text PDFJ Biol Chem
January 2025
Department of Biological Sciences, Indian Institute of Science Education and Research Berhampur, India. Electronic address:
Long Interspersed Nuclear Element 1 (LINE1/L1) retrotransposons, which comprise 17% of the human genome, typically remain inactive in healthy somatic cells but are reactivated in several cancers. We previously demonstrated that p53 silences L1 transposons in human somatic cells, potentially acting as a tumor-suppressive mechanism. However, the precise molecular mechanisms underlying p53-mediated repression of L1 and its life cycle intermediates remain unclear.
View Article and Find Full Text PDFCell
January 2025
Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Université libre de Bruxelles (ULB), Institut Jules Bordet, Brussels, Belgium. Electronic address:
The marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links N6-methyladenosine (mA), installed on RNA by the METTL3-METTL14 methyltransferase complex, to histone modifications, but the link between mA and DNA methylation remains scarcely explored. This study shows that METTL3-METTL14 recruits the DNA methyltransferase DNMT1 to chromatin for gene-body methylation.
View Article and Find Full Text PDFCancer Cell Int
January 2025
Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin 2nd Road, Shanghai, 20025, China.
Background: Methyltransferase-like (METTL) family protein plays a crucial role in the progression of malignancies. However, the function of METTL17 across pan-cancers, especially in hepatocellular carcinoma (HCC) is still poorly understood.
Methods: All original data were downloaded from TCGA, GTEx, HPA, UCSC databases and various data portals.
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