JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes.
JHDM1B is an evolutionarily conserved and ubiquitously expressed member of the JHDM (JmjC-domain-containing histone demethylase) family. Because it contains an F-box motif, this protein is also known as FBXL10 (ref. 4). With the use of a genome-wide RNAi screen, the JHDM1B worm orthologue (T26A5.5) was identified as a gene that regulates growth. In the mouse, four independent screens have identified JHDM1B as a putative tumour suppressor by retroviral insertion analysis. Here we identify human JHDM1B as a nucleolar protein and show that JHDM1B preferentially binds the transcribed region of ribosomal DNA to repress the transcription of ribosomal RNA genes. We also show that repression of ribosomal RNA genes by JHDM1B is dependent on its JmjC domain, which is necessary for the specific demethylation of trimethylated lysine 4 on histone H3 in the nucleolus. In agreement with the notion that ribosomal RNA synthesis and cell growth are coupled processes, we show a JmjC-domain-dependent negative effect of JHDM1B on cell size and cell proliferation. Because aberrant ribosome biogenesis and the disruption of epigenetic control mechanisms contribute to cellular transformation, these results, together with the low levels of JHDM1B expression found in aggressive brain tumours, suggest a role for JHDM1B in cancer development.
Frescas
David
D
Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
Guardavaccaro
Daniele
D
Bassermann
Florian
F
Koyama-Nasu
Ryo
R
Pagano
Michele
M
D002466:Cell Nucleolus / Q000378:metabolism*; D049109:Cell Proliferation; D004275:DNA, Ribosomal / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D044783:F-Box Proteins / Q000737:chemistry / Q000378:metabolism*; D020459:Genes, rRNA / Q000235:genetics*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D008745:Methylation; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic
D004275:DNA, Ribosomal; D044783:F-Box Proteins; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; D010089:Oxidoreductases, N-Demethylating