title: NML-mediated rRNA base methylation links ribosomal subunit formation to cell proliferation in a p53-dependent manner.
abstract: Ribosomal RNAs (rRNAs) act as scaffolds and ribozymes in ribosomes, and these functions are modulated by post-transcriptional modifications. However, the biological role of base methylation, a well-conserved modification of rRNA, is poorly understood. Here, we demonstrate that a nucleolar factor, nucleomethylin (NML; also known as RRP8), is required for the N(1)-methyladenosine (m(1)A) modification in 28S rRNAs of human and mouse cells. NML also contributes to 60S ribosomal subunit formation. Intriguingly, NML depletion increases 60S ribosomal protein L11 (RPL11) levels in the ribosome-free fraction and protein levels of p53 through an RPL11-MDM2 complex, which activates the p53 pathway. Consequently, the growth of NML-depleted cells is suppressed in a p53-dependent manner. These observations reveal a new biological function of rRNA base methylation, which links ribosomal subunit formation to p53-dependent inhibition of cell proliferation in mammalian cells.
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Waku
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan nakajima@tara.tsukuba.ac.jp.
authors.forename: Yuka
authors.identifier: 0000-0002-7357-2910
authors.initials: Y
authors.lastname: Nakajima
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Yokoyama
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Nomura
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kako
authors.affiliation: Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kobayashi
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000378:metabolism*; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins / Q000378:metabolism; D054683:Ribosome Subunits, Large, Eukaryotic / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; D008780:Methyltransferases; C529371:RRP8 protein, human
keywords: Cell proliferation; NML; Nucleolar factor; m1A; p53; rRNA modification