[A CxxC domain that binds to unmethylated CpG is required for KDM2A to control rDNA transcription].
Dysfunction of ribosome biogenesis is commonly found in cancers. Because the transcription of ribosomal RNA genes (rDNA) is a rate-limiting step in ribosome biogenesis and is elevated in many cancer cells, ribosomal RNA transcription can be a target for cancer therapy. In eukaryotes, ribosomal RNA is transcribed specifically in nucleoli by RNA polymerase I but not by RNA polymerase II. Therefore, ribosomal RNA transcription by RNA polymerase I would have a distinct nature compared to transcription by RNA polymerase II. Genomic DNA with proteins including histones constitutes chromatin. The structure of chromatin has plasticity and is regulated by chemical modifications of chromatin's components. We had reported that histone demethylase KDM2A reduced ribosomal RNA transcription in response to starvation. In this symposium, we reported our recent results showing the mechanism by which KDM2A was recruited to rDNA chromatin. We found that KDM2A bound to a rDNA promoter with unmethylated CpG dinucleotides via KDM2A CxxC-zinc finger motif. This binding was required for KDM2A to demethylate histone in the rDNA promoter and reduce rDNA transcription resulting from starvation. Further, this binding was detected before starvation, independent of the demethylase activity. We also found that the histone demethylation by KDM2A in response to starvation was detected only in the rDNA promoter, but not in a gene promoter transcribed by Pol II, the P2RX4 promoter. These results suggest that it is important to consider genome regions and cell conditions when developing epigenetic drugs.
Department of Molecular Pharmacology Faculty of Pharmacy, Takasaki University of Health and Welfare.
Makoto
M
Tsuneoka
Yuji
Y
Tanaka
Kengo
K
Okamoto
D018899:CpG Islands; D019175:DNA Methylation; D004275:DNA, Ribosomal / Q000378:metabolism*; D044783:F-Box Proteins / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
D004275:DNA, Ribosomal; D044783:F-Box Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human