Alternative titles; symbols
HGNC Approved Gene Symbol: NOLC1
Cytogenetic location: 10q24.32 Genomic coordinates (GRCh38) : 10:102,152,389-102,163,870 (from NCBI)
Using a monoclonal antibody-based strategy to search for nuclear proteins that fluctuate during the cell cycle, Pai et al. (1995) identified nucleolar protein p130. They cloned a cDNA encoding p130 by immunoscreening a human HL60 cDNA library. The predicted 699-amino acid protein contains a motif that consists of a long serine-rich stretch interspersed with acidic residues; this motif is repeated 10 times. The amino acid sequence of p130 is 74% identical to that of rat nucleolar protein Nopp140, with the N and C termini and the serine-acidic stretches showing the most conservation. Western blot analysis of purified p130 showed that it is a 130-kD protein that is converted to 95 kD by phosphatase treatment. A cellular casein kinase II (115440, 115441, 115442) activity is responsible for the highly phosphorylated state of p130. During mitosis, p130 may be subject to additional phosphorylation by cdc2 kinase (116940). By immunofluorescence, p130 is localized to the nucleoli of interphase cells but is undetectable in cells in the mitotic phase. P130 appears as dot-like granules that are assembled in the nucleoplasm at telophase and early G1-phase before migrating into the nucleoli to form part of the dense fibrillar component, the subnucleolar region for pre-rRNA synthesis and processing. Pai et al. (1995) suggested that the functions of p130 are related to nucleologenesis.
The human nuclear protein p130, which Chen et al. (1999) named NOPP140, is thought to shuttle between nucleolus and cytoplasm. However, the predominant nucleolar localization of NOPP140 homologs from different species suggests that NOPP140 is also involved in events occurring within the nucleolus. Chen et al. (1999) demonstrated that the largest subunit of RNA polymerase I, RPA194, coimmunoprecipitates with NOPP140. Double immunofluorescence showed that NOPP140 colocalizes with RNA polymerase I at the active foci of rRNA gene (rDNA) transcription in the nucleolus. These results suggest that NOPP140 can interact with RNA polymerase I in vivo. Transfected cells expressing the N-terminal half of NOPP140 displayed altered nucleoli with crescent-shaped structures. This phenotype is reminiscent of the segregated nucleoli induced by actinomycin D treatment, which is known to inhibit rRNA synthesis. Consistently, the N-terminal half of NOPP140 mislocalized the endogenous RNA polymerase I and shut off cellular rDNA transcription as revealed by an in situ run-on assay. These dominant-negative effects of the N-terminal half of NOPP140 suggest that NOPP140 plays an essential role in rDNA transcription. Ectopic expression of NOPP140 to a very high level caused the formation of a transcriptionally inactive spherical structure that occupied the entire nucleolar area and trapped RNA polymerase I, fibrillarin (FBL; 134795), and NOPP140 but excluded nucleolin (NCL; 164035). The mislocalizations of these nucleolar proteins after NOPP140 overexpression imply that NOPP140 may also play roles in maintenance of nucleolar integrity.
Spinal muscular atrophy (SMA; 253300) is an autosomal recessive neurodegenerative disease caused by reduced SMN (see SMN1; 600354) levels. The assembly machinery containing SMN is implicated in the biogenesis of the spliceosomal small nuclear ribonucleoproteins (snRNPs). SMN is present in both the cytoplasm and nucleus, where it transiently accumulates in subnuclear domains named Cajal bodies (CBs) and functions in the maturation of snRNPs and small nucleolar (sno)RNPs. Renvoise et al. (2009) showed that the U snRNA export factors PHAX (RNUXA; 604924) and CRM1 (XPO1; 602559) and the box C/D snoRNP core protein fibrillarin concentrated in CBs from SMA fibroblast cells, whereas the box H/ACA core proteins GAR1 (NOLA1; 606468) and NAP57/dyskerin (DKC1; 300126) showed reduced CB localization. The functional deficiency in SMA cells was associated with decreased localization of the snoRNP chaperone Nopp140 in CBs that correlated with disease severity. RNA interference knockdown experiments in control fibroblasts demonstrated that SMN was required for accumulation of Nopp140 in CBs. Conversely, overexpression of SMN in SMA cells restored the CB localization of Nopp140, whereas SMN mutants found in SMA patients were defective in promoting the association of Nopp140 with CBs. Renvoise et al. (2009) concluded that only a subset of CB functions was impaired in SMA cells and that a decrease of Nopp140 localization in CBs may be a phenotypic marker for SMA.
KBTBD8 (616607) functions as an adaptor for substrate recognition by the ubiquitin ligase CUL3 (603136). Using mass spectrometric analysis, Werner et al. (2015) found that KBTBD8 interacted with TCOF1 (606847) and NOLC1. CUL3-KBTBD8 monoubiquitinated TCOF1 and NOLC1 in a manner that required the cofactor beta-arrestin (see 107940). Knockdown of KBTBD8, TCOF1, or NOLC1 in human embryonic stem cells (hESCs) via short hairpin RNA inhibited hESC differentiation into neural crest cells and accelerated hESC differentiation into central nervous system (CNS) precursors. Affinity purification revealed that ubiquitinated TCOF1-NOLC1 complexes engaged RNA polymerase I into complexes with the small ribosomal processing complex. Werner et al. (2015) hypothesized that KBTBD8-dependent ubiquitination drives formation of a TCOF1-NOLC1 platform in hESCs that connects RNA polymerase I with ribosome modification enzymes at specific mRNAs to delay accumulation of CNS precursor proteins until neural crest specification has occurred.
Hartz (2015) mapped the NOLC1 gene to chromosome 10q24.32 based on an alignment of the NOLC1 sequence (GenBank BC001883) with the genomic sequence (GRCh38).
Chen, H.-K., Pai, C.-Y., Huang, J.-Y., Yeh, N.-H. Human Nopp140, which interacts with RNA polymerase I: implications for rRNA gene transcription and nucleolar structural organization. Molec. Cell. Biol. 19: 8536-8546, 1999. [PubMed: 10567578] [Full Text: https://doi.org/10.1128/MCB.19.12.8536]
Hartz, P. A. Personal Communication. Baltimore, Md. 10/21/2015.
Pai, C.-Y., Chen, H.-K., Sheu, H.-L., Yeh, N.-H. Cell cycle-dependent alterations of a highly phosphorylated nucleolar protein p130 are associated with nucleologenesis. J. Cell Sci. 108: 1911-1920, 1995. [PubMed: 7657714] [Full Text: https://doi.org/10.1242/jcs.108.5.1911]
Renvoise, B., Colasse, S., Burlet, P., Viollet, L., Meier, U. T., Lefebvre, S. The loss of the snoRNP chaperone Nopp140 from Cajal bodies of patient fibroblasts correlates with the severity of spinal muscular atrophy. Hum. Molec. Genet. 18: 1181-1189, 2009. [PubMed: 19129172] [Full Text: https://doi.org/10.1093/hmg/ddp009]
Werner, A., Iwasaki, S., McGourty, C. A., Medina-Ruiz, S., Teerikorpi, N., Fedrigo, I., Ingolia, N. T., Rape, M. Cell-fate determination by ubiquitin-dependent regulation of translation. Nature 525: 523-527, 2015. [PubMed: 26399832] [Full Text: https://doi.org/10.1038/nature14978]