NUCLEOLIN

Summary

NUCLEOLIN (nucleolin multifunctional protein, HGNC:7667) is a protein-coding gene on chromosome 2q37.1, encoding Nucleolin (P19338). Nucleolin is the major nucleolar protein of growing eukaryotic cells. It is a selective cancer dependency (DepMap: 87.7% of cell lines).

Nucleolin (NCL), a eukaryotic nucleolar phosphoprotein, is involved in the synthesis and maturation of ribosomes. It is located mainly in dense fibrillar regions of the nucleolus. Human NCL gene consists of 14 exons with 13 introns and spans approximately 11kb. The intron 11 of the NCL gene encodes a small nucleolar RNA, termed U20.

Source: NCBI Gene 4691 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 114 total
• Phenotypes (HPO): 1
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 87.7% of screened cell lines
• MANE Select transcript: NM_005381

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7667
Approved symbol	NUCLEOLIN
Name	nucleolin multifunctional protein
Location	2q37.1
Locus type	gene with protein product
Status	Approved
Aliases	C23, Nsr1
Ensembl gene	ENSG00000115053
Ensembl biotype	protein_coding
OMIM	164035
Entrez	4691

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 37 protein_coding, 9 retained_intron, 4 nonsense_mediated_decay

ENST00000322723, ENST00000356936, ENST00000417652, ENST00000436894, ENST00000453992, ENST00000454824, ENST00000461347, ENST00000466274, ENST00000484328, ENST00000494618, ENST00000676514, ENST00000676690, ENST00000676798, ENST00000676913, ENST00000677703, ENST00000677786, ENST00000678131, ENST00000678246, ENST00000678364, ENST00000678405, ENST00000678729, ENST00000678828, ENST00000678849, ENST00000679348, ENST00000896138, ENST00000896139, ENST00000896140, ENST00000896141, ENST00000896142, ENST00000896143, ENST00000896144, ENST00000896145, ENST00000896146, ENST00000933632, ENST00000933633, ENST00000933634, ENST00000933635, ENST00000933636, ENST00000933637, ENST00000933638, ENST00000933639, ENST00000933640, ENST00000933641, ENST00000933642, ENST00000933643, ENST00000933644, ENST00000933645, ENST00000968621, ENST00000968622, ENST00000968623

RefSeq mRNA: 1 — MANE Select: NM_005381 NM_005381

CCDS: CCDS33397

Canonical transcript exons

ENST00000322723 — 14 exons

Exon	Start	End
ENSE00001889007	231464336	231464484
ENSE00001918315	231453531	231455267
ENSE00003491987	231458266	231458389
ENSE00003552021	231455401	231455624
ENSE00003573152	231461540	231462017
ENSE00003576400	231460152	231460293
ENSE00003582671	231457001	231457124
ENSE00003602640	231460478	231460564
ENSE00003605579	231457643	231457800
ENSE00003625107	231456010	231456136
ENSE00003638365	231456631	231456764
ENSE00003644527	231460669	231460866
ENSE00003662537	231463200	231463316
ENSE00003664513	231459001	231459125

Expression profiles

Bgee: expression breadth ubiquitous, 165 present calls, max score 99.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 542.5766 / max 11942.2071, expressed in 1828 samples.

FANTOM5 promoters (25 alternative TSS)

Promoter ID	TPM avg	Samples expressed
34523	466.8968	1827
34510	21.7979	1693
34522	8.5001	1721
34508	7.6546	1538
34511	4.6810	1371
34521	4.2227	1343
202602	3.1444	1171
34507	2.9453	1127
34517	2.4937	1015
34504	2.4223	1077

Top tissues by expression

256 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.46	gold quality
ganglionic eminence	UBERON:0004023	99.45	gold quality
cortical plate	UBERON:0005343	99.41	gold quality
vermiform appendix	UBERON:0001154	99.25	gold quality
body of pancreas	UBERON:0001150	99.22	gold quality
smooth muscle tissue	UBERON:0001135	99.21	gold quality
calcaneal tendon	UBERON:0003701	99.14	gold quality
right ovary	UBERON:0002118	99.13	gold quality
left ovary	UBERON:0002119	99.13	gold quality
colonic epithelium	UBERON:0000397	99.10	gold quality
sural nerve	UBERON:0015488	99.05	gold quality
body of uterus	UBERON:0009853	99.03	gold quality
rectum	UBERON:0001052	99.02	gold quality
left uterine tube	UBERON:0001303	99.02	gold quality
skin of abdomen	UBERON:0001416	99.00	gold quality
skin of leg	UBERON:0001511	98.96	gold quality
mucosa of stomach	UBERON:0001199	98.95	gold quality
stromal cell of endometrium	CL:0002255	98.94	gold quality
left adrenal gland	UBERON:0001234	98.94	gold quality
endocervix	UBERON:0000458	98.93	gold quality
right adrenal gland	UBERON:0001233	98.93	gold quality
tibial nerve	UBERON:0001323	98.92	gold quality
ectocervix	UBERON:0012249	98.92	gold quality
right adrenal gland cortex	UBERON:0035827	98.92	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.90	gold quality
left adrenal gland cortex	UBERON:0035825	98.89	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.87	gold quality
body of stomach	UBERON:0001161	98.84	gold quality
right lobe of thyroid gland	UBERON:0001119	98.81	gold quality
descending thoracic aorta	UBERON:0002345	98.81	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	22.08
E-CURD-122	yes	19.46
E-MTAB-10042	yes	14.03
E-CURD-112	yes	10.35
E-MTAB-8271	yes	9.90
E-GEOD-130148	yes	7.90
E-MTAB-9801	yes	6.05
E-MTAB-9689	no	1802.89
E-MTAB-7606	no	1698.89
E-MTAB-7407	no	1325.02
E-GEOD-100618	no	677.02
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

54 targeting NUCLEOLIN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-3153	99.55	67.59	2337

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 87.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Anchorage of HIV particles on permissive cells induces aggegation of surface nucleolin and its association with detergent-insoluble lipid raft components. Moreover, surface nucleolin and lipid rafts are implicated in the HIV entry process. (PMID:12027446)
• functions in the biogenesis and/or trafficking of hY1 and hY3 RNPs through the nucleolus and subsequent transport to the cytoplasm (PMID:12096904)
• These data indicate a novel p53-dependent mechanism in which cell stress mobilizes nucleolin for transient replication inhibition and DNA repair. (PMID:12138209)
• results suggest that the cell surface-expressed nucleolin serves as a low affinity receptor for midkine and could be implicated in its entry process (PMID:12147681)
• change in levels and localization accompanies apoptosis in leukemia cells (PMID:12506112)
• Data suggest that changes in nucleolin or argyrophilic nucleolar organizer region proteins occur in cells induced to undergo apoptosis by okadaic acid and by other stimuli. (PMID:12559966)
• Results show that nucleolin interacts with centaurin-alpha(1) protein, suggesting that centaurin-alpha(1) may be part of a ribonucleoprotein complex. (PMID:12565890)
• Bidirectional DNA unwinding is achieved by a ternary complex of T antigen, this protein and DNA topoisomerase I. (PMID:12634843)
• we propose a autoregulatory model in which Nucleolin regulates the translation of Nucleolin mRNA, such that during a period of excess protein, translation is inhibited through direct binding of Nucleolin protein to its mRNA. (PMID:12804115)
• The cell surface molecule recognized by F3 is nucleolin. Nucleolin specifically bound to an F3 peptide affinity matrix from extracts of cultured breast carcinoma cells. (PMID:14638862)
• nucleolin functions as a bcl-2-stabilizing factor and that taxol and okadaic acid treatment induces apoptosis in HL-60 cells through a process that involves down-regulation of nucleolin and destabilization of bcl-2 mRNA (PMID:14679209)
• interaction of hTERT and nucleolin participates in the dynamic intracellular localization of telomerase complex (PMID:15371412)
• Retinoic acid-induced apoptosis is a consequence of cellular differentiation, which leads to nucleolin down-regulation and bcl-2 mRNA instability. (PMID:15492114)
• identification of N317 and N492 as the two N-glycosylation sites (PMID:15823039)
• Nucleolin was detected at the surface of macrophages, and anti-nucleolin antibody inhibited the binding of the early apoptotic cells to macrophages. (PMID:16135517)
• RNA/protein interaction studies show binding of nucleolin to 3’UTR may be of major importance for increased efficiency of MMP-9 translation.MMP-9 expression can be regulated posttranscriptionally, affecting efficiency of translation & localization of mRNA (PMID:16153722)
• results demonstrate that PTN inhibits HIV infection and suggest that the cell surface-expressed nucleolin is a low affinity receptor for PTN binding to cells and it is also implicated in PTN entry into cells by an active process (PMID:16156786)
• nucleolin and poly[ADP-ribosyl] transferase have roles in drug resistance (PMID:16212410)
• Changes in the subcellular distribution and expression level of nucleolin play an important role in intestinal cell differentiation and relay the signaling pathway induced by laminin-1. (PMID:16245305)
• The present results indicate that PP1 and nucleolin were differently expressed at G(1)/S and G(2)/M boundaries of the cell cycle and acted in a different fashion during cell-cycle progression. (PMID:16329155)
• VEGF, extracellular matrix, and intracellular motor protein MyH9 are all essential for the novel function of nucleolin in angiogenesis. (PMID:16403913)
• 3’UTR-bound nucleolin enhances mRNA stability of beta-globin (PMID:16508016)
• nucleolin binds the KLF2 promoter (PMID:16571724)
• In cells transfected with both IRF-2 and p300/CBP-associated factor , IRF-2 associated with endogenous nucleolin. (PMID:16582966)
• Nucleolin greatly enhances the activity of the chromatin remodeling machineries SWI/SNF and ACF (PMID:16601700)
• intracellular distribution of nucleolin in epithelial cells is Rb-dependent, and an altered nucleolin localization in human cancerous tissues results from a loss of Rb (PMID:16698799)
• nucleolin, like ARF, responds to hyperproliferative signals by upregulation of p53 through Hdm2 inhibition (PMID:16751805)
• cross-dependence between aprataxin and nucleolin in the nucleolus (PMID:16777843)
• data provide evidence of a nucleolar localization of K-Ras4B and describe a functional association between K-Ras4B and nucleolin (PMID:16889753)
• The functional consequences of the identified PIDD/nucleolin interaction remain to be elucidated, but may be related to a recently discovered new role for PIDD in the activation of NF-kappaB upon genotoxic stress. (PMID:16982033)
• Nucleolin was identified as a protein that allows RNA polymerase II to transcribe nucleosomal templates in vitro. (PMID:17130237)
• nucleolin acts as a component of the gene regulation program of CD34-positive hematopoietic (PMID:17255095)
• Results indicate that nucleolin is required for nucleolus formation, and is also involved in chromosome congression and spindle formation. (PMID:17535846)
• Nucleolin interacts with the AP-1 site within the promoter sequence of the metalloproteinase-13 gene. (PMID:17626252)
• The repressive activity of GZF1 is modulated by the level at which nucleolin is expressed. (PMID:17674968)
• Data show that, in addition to the expected effects on pre-ribosomal RNA accumulation and nucleolar structure, the absence of nucleolin results in a cell growth arrest, accumulation in G2, and an increase of apoptosis. (PMID:17692122)
• a novel function of Influenza A virus NS1, namely, affecting cellular events via interaction with nucleolin (PMID:17767916)
• Evidence that BIG1 and nucleolin, but not fibrillarin, can be present with p62 at the nuclear envelope confirms the presence of BIG1 and nucleolin in dynamic molecular complexes that change in composition while moving through nuclei (PMID:18292223)
• the nucleolus exhibits an osmotically regulated gatekeeping activity that controls the spatial dynamics and functions of nucleolin (PMID:18299322)
• Using small interfering RNA technology, we show that viral replication requires a high level of nucleolin expression, demonstrating for the first time a direct role for a nucleolar protein in herpes simplex virus biology. (PMID:18321972)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ncl	ENSMUSG00000026234
rattus_norvegicus	Ncl	ENSRNOG00000018273

Paralogs (36): DAZAP1 (ENSG00000071626), CIRBP (ENSG00000099622), RBM23 (ENSG00000100461), RBM3 (ENSG00000102317), TIA1 (ENSG00000116001), HNRNPA2B1 (ENSG00000122566), RBM19 (ENSG00000122965), RBM39 (ENSG00000131051), MSI1 (ENSG00000135097), HNRNPA1 (ENSG00000135486), HNRNPD (ENSG00000138668), HNRNPA1L2 (ENSG00000139675), RBMX (ENSG00000147274), A1CF (ENSG00000148584), TIAL1 (ENSG00000151923), RBM46 (ENSG00000151962), HNRNPDL (ENSG00000152795), MSI2 (ENSG00000153944), RBM47 (ENSG00000163694), RBMY1F (ENSG00000169800), HNRNPA3 (ENSG00000170144), RBMXL2 (ENSG00000170748), RBM4B (ENSG00000173914), RBM4 (ENSG00000173933), RBMXL3 (ENSG00000175718), HNRNPA0 (ENSG00000177733), TRNAU1AP (ENSG00000180098), HNRNPAB (ENSG00000197451), RBMXL1 (ENSG00000213516), HNRNPA1L3 (ENSG00000224578), RBMY1J (ENSG00000226941), RBMY1A1 (ENSG00000234414), RBMY1E (ENSG00000242389), RBMY1B (ENSG00000242875), RBMY1D (ENSG00000244395), DND1 (ENSG00000256453)

Protein

Protein identifiers

Nucleolin — P19338 (reviewed: P19338)

Alternative names: Protein C23

All UniProt accessions (11): P19338, A0A7I2V2S8, A0A7I2V2U7, A0A7I2V349, A0A7I2V3F3, A0A7I2V428, A0A7I2V506, A0A7I2V5M5, A0A7I2V699, C9JLB1, H7BY16

UniProt curated annotations — full annotation on UniProt →

Function. Nucleolin is the major nucleolar protein of growing eukaryotic cells. It is found associated with intranucleolar chromatin and pre-ribosomal particles. It induces chromatin decondensation by binding to histone H1. It is thought to play a role in pre-rRNA transcription and ribosome assembly. May play a role in the process of transcriptional elongation. Binds RNA oligonucleotides with 5’-UUAGGG-3’ repeats more tightly than the telomeric single-stranded DNA 5’-TTAGGG-3’ repeats.

Subunit / interactions. Identified in a IGF2BP1-dependent mRNP granule complex containing untranslated mRNAs. Component of the SWAP complex that consists of NPM1, NCL/nucleolin, PARP1 and SWAP70. Component of a complex which is at least composed of HTATSF1/Tat-SF1, the P-TEFb complex components CDK9 and CCNT1, RNA polymerase II, SUPT5H, and NCL/nucleolin. Interacts with AICDA. Interacts with APTX. Interacts with C1QBP. Interacts with ERBB4. Interacts (via C-terminus) with FMR1 isoform 6 (via N-terminus). Interacts with GZF1; this interaction is important for nucleolar localization of GZF1. Interacts with NSUN2. Interacts with NVL. Interacts (via N-terminus domain) with SETX. Interacts (via RRM1 and C-terminal RRM4/Arg/Gly-rich domains) with TERT; the interaction is important for nucleolar localization of TERT. Interacts with WDR46. Interacts with ZFP36. Interacts with LRRC34. Interacts with RRP1B. Interacts with HNRNPU; this interaction occurs during mitosis. Interacts with RIOK1; RIOK1 recruits NCL to PRMT5 for symmetrically methylation. Interacts with ZBTB7B. Interacts with MDK; this interaction promotes NCL clustering and lateral movements of this complex into lipid rafts leading to MDK internalization. Interacts with HDGF (isoform 1). Interacts with ALKBH2. Interacts with IGFBP5; this interaction is necessary for IGFBP5 localization to the nucleus. Interacts with DDX24 (when ubiquitinated); this interaction may be important during ribosome biogenesis.

Subcellular location. Nucleus. Nucleolus. Cytoplasm.

Post-translational modifications. Some glutamate residues are glycylated by TTLL8. This modification occurs exclusively on glutamate residues and results in a glycine chain on the gamma-carboxyl group. Symmetrically methylated by PRMT5.

RefSeq proteins (1): NP_005372* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000504	RRM_dom	Domain
IPR003954	RRM_euk-type	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR034230	Nucleolin_RRM1	Domain
IPR034233	Nucleolin_RRM2	Domain
IPR034234	Nucleolin_RRM3	Domain
IPR034235	Nucleolin_RRM4	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily

Pfam: PF00076

UniProt features (139 total): modified residue 61, strand 23, cross-link 11, helix 10, compositionally biased region 10, repeat 8, domain 4, sequence variant 3, sequence conflict 3, region of interest 3, initiator methionine 1, chain 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
9CB5	X-RAY DIFFRACTION	2.6
2FC8	SOLUTION NMR
2FC9	SOLUTION NMR
2KRR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19338-F1	62.84	0.04

Antibody-complex structures (SAbDab): 1 — 9CB5

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (72): 9, 15, 16, 28, 34, 41, 42, 67, 69, 76, 84, 92, 96, 99, 102, 106, 109, 113, 116, 121 …

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol
R-HSA-9820960	Respiratory syncytial virus (RSV) attachment and entry
R-HSA-9918476	Assembly and Release of Dengue Virus Virions

MSigDB gene sets: 342 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, E2F_Q4, E2F_Q4_01, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MORF_SMC1L1, PID_TELOMERASE_PATHWAY, E2F4DP1_01, GOBP_RESPONSE_TO_PEPTIDE, MODULE_151, GCM_NPM1, MORF_SNRP70, MORF_UBE2I, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP

GO Biological Process (11): angiogenesis (GO:0001525), negative regulation of translation (GO:0017148), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of insulin receptor signaling pathway (GO:0046627), positive regulation of mRNA splicing, via spliceosome (GO:0048026), cellular response to epidermal growth factor stimulus (GO:0071364), positive regulation of transcription of nucleolar large rRNA by RNA polymerase I (GO:1901838), cellular response to leukemia inhibitory factor (GO:1990830), regulation of gene expression (GO:0010468), positive regulation of macromolecule biosynthetic process (GO:0010557), regulation of RNA metabolic process (GO:0051252)

GO Molecular Function (10): RNA binding (GO:0003723), telomeric repeat DNA binding (GO:0042162), PH domain binding (GO:0042731), identical protein binding (GO:0042802), insulin receptor substrate binding (GO:0043560), DNA topoisomerase binding (GO:0044547), mRNA 5’-UTR binding (GO:0048027), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (14): cornified envelope (GO:0001533), nucleus (GO:0005634), nucleoplasm (GO:0005654), spliceosomal complex (GO:0005681), chromosome (GO:0005694), nucleolus (GO:0005730), plasma membrane (GO:0005886), cell cortex (GO:0005938), membrane (GO:0016020), cytoplasmic ribonucleoprotein granule (GO:0036464), extracellular exosome (GO:0070062), macropinosome membrane (GO:0160056), ribonucleoprotein complex (GO:1990904), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
rRNA processing in the nucleus and cytosol	1
Respiratory Syncytial Virus Infection Pathway	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of macromolecule biosynthetic process	2
nucleic acid binding	2
protein binding	2
binding	2
nuclear lumen	2
intracellular membraneless organelle	2
cell periphery	2
cytoplasm	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
translation	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
insulin receptor signaling pathway	1
negative regulation of signal transduction	1
regulation of insulin receptor signaling pathway	1
negative regulation of cellular response to insulin stimulus	1
mRNA splicing, via spliceosome	1
positive regulation of RNA splicing	1
regulation of mRNA splicing, via spliceosome	1
positive regulation of mRNA processing	1
response to epidermal growth factor	1
cellular response to growth factor stimulus	1
nucleolar large rRNA transcription by RNA polymerase I	1
positive regulation of transcription by RNA polymerase I	1
regulation of transcription of nucleolar large rRNA by RNA polymerase I	1
cellular response to cytokine stimulus	1
response to leukemia inhibitory factor	1
gene expression	1
macromolecule biosynthetic process	1
positive regulation of biosynthetic process	1
positive regulation of macromolecule metabolic process	1
RNA metabolic process	1
regulation of nucleobase-containing compound metabolic process	1
regulation of macromolecule metabolic process	1

Protein interactions and networks

STRING

4258 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NUCLEOLIN	NPM1	P06748	999
NUCLEOLIN	FBL	P22087	990
NUCLEOLIN	HNRNPK	P61978	986
NUCLEOLIN	YY1	P25490	968
NUCLEOLIN	CALR	P27797	962
NUCLEOLIN	MDK	P21741	942
NUCLEOLIN	YBX1	P16990	919
NUCLEOLIN	COL18A1	P39060	914
NUCLEOLIN	MYC	P01106	892
NUCLEOLIN	RIOK1	Q9BRS2	890
NUCLEOLIN	HNRNPD	P07029	888
NUCLEOLIN	PTBP1	P26599	877
NUCLEOLIN	RRP1	P56182	862
NUCLEOLIN	PARK7	Q99497	856
NUCLEOLIN	EGFR	P00533	855

IntAct

513 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
BRAF	KRAS	psi-mi:“MI:0914”(association)	0.680
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCL	H1-5	psi-mi:“MI:0915”(physical association)	0.560
SMNDC1	NCL	psi-mi:“MI:0915”(physical association)	0.540
RPL37A	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
MAP2K2	BAG2	psi-mi:“MI:0914”(association)	0.530
NCL	Ankrd1	psi-mi:“MI:0915”(physical association)	0.520
NFE4	PRMT5	psi-mi:“MI:0914”(association)	0.520
RRP1B	NPM1	psi-mi:“MI:0914”(association)	0.510
NCL	RRP1B	psi-mi:“MI:0403”(colocalization)	0.510
NCL		psi-mi:“MI:0915”(physical association)	0.500
ARFGEF1	NCL	psi-mi:“MI:0915”(physical association)	0.500
ARFGEF1	NCL	psi-mi:“MI:0914”(association)	0.500
NCL	KHDRBS1	psi-mi:“MI:0914”(association)	0.500
KHDRBS1	NCL	psi-mi:“MI:0914”(association)	0.500
NCL	KHDRBS1	psi-mi:“MI:0915”(physical association)	0.500
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
MYH9	NCL	psi-mi:“MI:0915”(physical association)	0.460

BioGRID (1189): PIK3R1 (Affinity Capture-Western), NCL (Affinity Capture-Western), HNRNPD (Affinity Capture-Western), NCL (Affinity Capture-Western), NCL (Affinity Capture-MS), NCL (Affinity Capture-Western), NCL (Affinity Capture-MS), NCL (Affinity Capture-Western), NCL (Reconstituted Complex), NCL (Affinity Capture-MS), NCL (Affinity Capture-Western), NCL (Biochemical Activity), NCL (Protein-peptide), NCL (Affinity Capture-MS), NCL (Affinity Capture-MS)

ESM2 similar proteins: A2ZDX4, A2ZDX6, A2ZDX8, A2ZDX9, A8CVF3, B1NY81, O04132, P09406, P0A0V6, P0A0V7, P12948, P12949, P12950, P12951, P12952, P19338, P21298, P22238, P22239, P22240, P25863, P28639, P28640, P28641, P28783, P30185, P30287, P31168, P40159, P42758, P42759, P42763, P46524, P46525, P46526, Q00742, Q07202, Q07322, Q2R4Z4, Q2R4Z5

Diamond homologs: A0A0D1C8Z4, A0A2R8Y4L2, A5A6H4, A7VJC2, D0VWM8, G5EFS2, O14979, O43347, O88569, O89086, O93235, O94432, P04256, P07909, P09405, P09651, P09867, P13383, P17130, P19338, P19682, P19683, P21522, P22626, P28644, P41891, P48809, P48810, P49312, P51968, P51989, P51990, P51991, P51992, P60824, P60825, P60826, P98179, Q02926, Q03878

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
NCL	“down-regulates activity”	MYBL1	binding
NCL	“down-regulates activity”	MYB	binding
NCL	“up-regulates quantity by expression”	HBB	“post transcriptional regulation”
PTEN	“up-regulates activity”	NCL	dephosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 198 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Signaling by high-kinase activity BRAF mutants	5	11.8×	8e-03
Signaling by ALK fusions and activated point mutants	9	10.0×	2e-04
rRNA modification in the nucleus and cytosol	6	8.3×	1e-02
Cargo recognition for clathrin-mediated endocytosis	8	6.2×	8e-03
MAPK family signaling cascades	8	6.1×	8e-03
Diseases of signal transduction by growth factor receptors and second messengers	13	5.5×	3e-04
Neddylation	12	4.2×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	7	14.9×	2e-04
mitophagy	7	13.2×	3e-04
ribosomal large subunit biogenesis	5	13.2×	4e-03
cellular response to estradiol stimulus	5	12.2×	5e-03
G1/S transition of mitotic cell cycle	9	10.8×	8e-05
cellular response to UV	6	10.6×	3e-03
cellular senescence	6	10.6×	3e-03
autophagosome maturation	5	10.4×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

114 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	10
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

1861 predictions. Top by Δscore:

Variant	Effect	Δscore
2:231455264:CGCC:C	acceptor_gain	1.0000
2:231455266:CC:C	acceptor_gain	1.0000
2:231455267:CC:C	acceptor_gain	1.0000
2:231455268:C:CC	acceptor_gain	1.0000
2:231455268:CT:C	acceptor_loss	1.0000
2:231455272:A:T	acceptor_gain	1.0000
2:231455395:CCTTA:C	donor_loss	1.0000
2:231455396:CTTA:C	donor_loss	1.0000
2:231455397:TTACC:T	donor_loss	1.0000
2:231455399:A:C	donor_loss	1.0000
2:231455620:CAAAC:C	acceptor_gain	1.0000
2:231455621:AAAC:A	acceptor_gain	1.0000
2:231455622:AAC:A	acceptor_gain	1.0000
2:231455623:AC:A	acceptor_gain	1.0000
2:231455624:CC:C	acceptor_gain	1.0000
2:231455625:C:CC	acceptor_gain	1.0000
2:231455994:CG:C	donor_gain	1.0000
2:231455998:T:TA	donor_gain	1.0000
2:231456003:C:A	donor_gain	1.0000
2:231456005:CTTA:C	donor_loss	1.0000
2:231456006:TTA:T	donor_loss	1.0000
2:231456007:TA:T	donor_loss	1.0000
2:231456008:A:AC	donor_gain	1.0000
2:231456008:A:AG	donor_loss	1.0000
2:231456008:AC:A	donor_gain	1.0000
2:231456009:C:CC	donor_gain	1.0000
2:231456009:CC:C	donor_gain	1.0000
2:231456043:AT:A	donor_gain	1.0000
2:231456044:T:A	donor_gain	1.0000
2:231456049:G:A	donor_gain	1.0000

AlphaMissense

4709 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:231455523:G:T	A645D	1.000
2:231455527:A:G	W644R	1.000
2:231455527:A:T	W644R	1.000
2:231455532:A:C	L642W	1.000
2:231455532:A:G	L642S	1.000
2:231455538:A:T	V640D	1.000
2:231455553:A:C	I635S	1.000
2:231455553:A:T	I635N	1.000
2:231455580:G:T	A626D	1.000
2:231455589:G:T	A623D	1.000
2:231455606:G:C	F617L	1.000
2:231455606:G:T	F617L	1.000
2:231455607:A:G	F617S	1.000
2:231455608:A:G	F617L	1.000
2:231455613:A:T	V615E	1.000
2:231455615:A:C	F614L	1.000
2:231455615:A:T	F614L	1.000
2:231455616:A:C	F614C	1.000
2:231455616:A:G	F614S	1.000
2:231455617:A:C	F614V	1.000
2:231455617:A:G	F614L	1.000
2:231455617:A:T	F614I	1.000
2:231455619:C:A	G613V	1.000
2:231455619:C:T	G613D	1.000
2:231455620:C:G	G613R	1.000
2:231455621:A:C	F612L	1.000
2:231455621:A:T	F612L	1.000
2:231455622:A:C	F612C	1.000
2:231455622:A:G	F612S	1.000
2:231455623:A:G	F612L	1.000

dbSNP variants (sampled 300 via entrez): RS1000048639 (2:231461769 G>A), RS1000161163 (2:231453318 T>C), RS1000334470 (2:231458013 A>G), RS1000589059 (2:231462995 T>A,C), RS1000847502 (2:231453142 G>A,C), RS1000961296 (2:231462781 T>G), RS1001034182 (2:231463461 C>A,T), RS1001188745 (2:231454166 T>C), RS1001666425 (2:231453547 G>A,C), RS1002010858 (2:231463059 G>A,C,T), RS1002041908 (2:231463335 GATC>G), RS1002453816 (2:231463920 C>T), RS1002548644 (2:231464760 G>A), RS1002618271 (2:231463773 G>A,C), RS1002672550 (2:231454397 C>A,T)

Disease associations

OMIM: gene MIM:164035 | disease phenotypes: MIM:209850

GenCC curated gene-disease

Mondo (1): autism (MONDO:0005260)

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000717	Autism

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001959_2	Eating disorders (purging via substances)	7.000000e-07
GCST002048_4	Attention deficit hyperactivity disorder	6.000000e-09
GCST003006_1	Hearing loss in noise exposure	5.000000e-07
GCST005182_2	Common carotid intima-media thickness in HIV negative individuals	6.000000e-06
GCST008839_452	Height	3.000000e-15
GCST90000025_884	Appendicular lean mass	3.000000e-33
GCST90020026_151	Hip index	5.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004980	appendicular lean mass
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295725 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.55	Kd	2795	nM	CHEMBL3752910
5.55	ED50	2795	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 11 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148834: Binding affinity to human NCL incubated for 45 mins by Kinobead based pull down assay	kd	2.7948	uM

CTD chemical–gene interactions

87 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression	4
sodium arsenite	increases stability, decreases expression, increases abundance, increases sumoylation, affects localization (+3 more)	4
Arsenic	affects methylation, increases expression, increases abundance	3
Estradiol	affects phosphorylation, increases expression	3
cobaltous chloride	decreases expression	2
Fulvestrant	decreases expression, affects cotreatment, increases methylation	2
Caffeine	increases expression, increases phosphorylation	2
Cannabidiol	affects cotreatment, increases expression	2
Plant Extracts	affects cotreatment, increases expression, decreases expression	2
UF010 compound	increases acetylation	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
moringin	affects cotreatment, increases expression	1
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
deoxynivalenol	increases expression	1
pyrogallol 1,3-dimethyl ether	increases expression, decreases expression, affects cotreatment, affects localization	1
beta-lapachone	decreases expression	1
afimoxifene	decreases expression	1
butyraldehyde	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
butylidenephthalide	decreases expression	1
cadmium acetate	decreases expression	1
coumarin	decreases phosphorylation	1
cupric oxide	increases expression	1
nivalenol	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
cyclic 3’,5’-uridine monophosphate	affects binding	1
arsenic trichloride	affects localization, affects binding, increases reaction	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4119053	Binding	Binding affinity to NCL in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1YA	Abcam HeLa NCL KO	Cancer cell line	Female
CVCL_KT80	HeLa SilenciX NCL	Cancer cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms