ESPL1

Summary

ESPL1 (extra spindle pole bodies like 1, separase, HGNC:16856) is a protein-coding gene on chromosome 12q13.13, encoding Separin (Q14674). Caspase-like protease, which plays a central role in the chromosome segregation by cleaving the SCC1/RAD21 subunit of the cohesin complex at the onset of anaphase. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

Stable cohesion between sister chromatids before anaphase and their timely separation during anaphase are critical for chromosome inheritance. In vertebrates, sister chromatid cohesion is released in 2 steps via distinct mechanisms. The first step involves phosphorylation of STAG1 (MIM 604358) or STAG2 (MIM 300826) in the cohesin complex. The second step involves cleavage of the cohesin subunit SCC1 (RAD21; MIM 606462) by ESPL1, or separase, which initiates the final separation of sister chromatids (Sun et al., 2009 [PubMed 19345191]).

Source: NCBI Gene 9700 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 264 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_012291

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16856
Approved symbol	ESPL1
Name	extra spindle pole bodies like 1, separase
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0165, ESP1, SEPA
Ensembl gene	ENSG00000135476
Ensembl biotype	protein_coding
OMIM	604143
Entrez	9700

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 5 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000257934, ENST00000535123, ENST00000549154, ENST00000550026, ENST00000552600, ENST00000552671, ENST00000553016, ENST00000553219, ENST00000920820, ENST00000920821, ENST00000960796

RefSeq mRNA: 1 — MANE Select: NM_012291 NM_012291

CCDS: CCDS8852

Canonical transcript exons

ENST00000257934 — 31 exons

Exon	Start	End
ENSE00001518398	53293273	53293638
ENSE00001560364	53268299	53268377
ENSE00002620441	53268755	53268847
ENSE00003482464	53270678	53270798
ENSE00003488273	53292806	53292970
ENSE00003507194	53281507	53281626
ENSE00003508656	53277083	53277227
ENSE00003514921	53288538	53288699
ENSE00003520699	53279732	53279866
ENSE00003526554	53277470	53277608
ENSE00003530849	53283129	53283257
ENSE00003536581	53285924	53286912
ENSE00003540596	53290085	53290212
ENSE00003546394	53292278	53292393
ENSE00003547730	53274817	53275010
ENSE00003558471	53270378	53270482
ENSE00003571883	53277821	53277960
ENSE00003574606	53287972	53288341
ENSE00003583781	53292574	53292657
ENSE00003586692	53272721	53272857
ENSE00003589180	53276620	53276859
ENSE00003597607	53289404	53289594
ENSE00003597662	53290841	53290996
ENSE00003605219	53284058	53284167
ENSE00003615525	53291690	53291860
ENSE00003636748	53283382	53283538
ENSE00003637219	53289090	53289303
ENSE00003673389	53290347	53290469
ENSE00003678759	53282264	53282435
ENSE00003678966	53269024	53270085
ENSE00003682842	53291984	53292088

Expression profiles

Bgee: expression breadth ubiquitous, 199 present calls, max score 98.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.1875 / max 79.5993, expressed in 1100 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125730	5.0821	1036
125729	0.7036	415
125731	0.2630	133
125733	0.1299	34
125732	0.0090	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.07	gold quality
oocyte	CL:0000023	97.75	gold quality
lower esophagus mucosa	UBERON:0035834	96.62	gold quality
esophagus squamous epithelium	UBERON:0006920	94.71	gold quality
epithelium of esophagus	UBERON:0001976	93.94	gold quality
ventricular zone	UBERON:0003053	91.10	gold quality
squamous epithelium	UBERON:0006914	90.87	gold quality
esophagus mucosa	UBERON:0002469	90.62	gold quality
tongue squamous epithelium	UBERON:0006919	89.33	gold quality
jejunal mucosa	UBERON:0000399	88.55	gold quality
cervix squamous epithelium	UBERON:0006922	87.53	gold quality
oral cavity	UBERON:0000167	86.94	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.26	gold quality
endometrium epithelium	UBERON:0004811	85.85	gold quality
ileal mucosa	UBERON:0000331	85.10	gold quality
embryo	UBERON:0000922	84.84	gold quality
gingival epithelium	UBERON:0001949	83.98	gold quality
amniotic fluid	UBERON:0000173	83.55	gold quality
pharyngeal mucosa	UBERON:0000355	83.40	gold quality
gingiva	UBERON:0001828	83.36	gold quality
ganglionic eminence	UBERON:0004023	83.09	gold quality
cartilage tissue	UBERON:0002418	81.85	gold quality
duodenum	UBERON:0002114	80.71	gold quality
sperm	CL:0000019	80.60	silver quality
cervix epithelium	UBERON:0004801	79.94	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.46	gold quality
male germ cell	CL:0000015	79.35	silver quality
trabecular bone tissue	UBERON:0002483	78.30	gold quality
thymus	UBERON:0002370	77.62	gold quality
buccal mucosa cell	CL:0002336	77.46	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	11.70
E-ANND-3	yes	5.39

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

30 targeting ESPL1, 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-3163	100.00	77.23	8605
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-3171	99.49	69.06	776
HSA-MIR-629-5P	98.78	68.72	1032
HSA-MIR-655-5P	98.74	65.93	888
HSA-MIR-34B-3P	98.70	67.40	1171
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-3188	98.58	65.60	878
HSA-MIR-4773	98.35	67.30	1710
HSA-MIR-6831-5P	98.26	67.20	990
HSA-MIR-541-5P	98.24	67.77	1181
HSA-MIR-3159	97.94	66.79	1098
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-3927-3P	97.68	66.76	892
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-6813-3P	95.78	63.78	540

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• Data suggest that separase is required for sister chromatid separation during mitosis in human cells, and that securin inhibits separase by blocking the access of substrates to the active site of separase. (PMID:12194817)
• Anaphase specific auto-cleavage of separase. (PMID:12297314)
• Processing, localization, and requirement of separase for normal anaphase progression. (PMID:12672959)
• density map at a resolution of 25 A of negatively stained separase-securin complex (PMID:15880121)
• Separase function is not restricted to anaphase initiation; its role in promoting loss of sister chromatid cohesion might be preferentially at arms but not centromeres. (PMID:16177575)
• nuclear exclusion is important to prevent cohesin cleavage during interphase in the absence of securin and the phosphorylation inhibition (PMID:17102637)
• Protein phosphatase 2A and separase form a complex regulated by separase autocleavage (PMID:17604273)
• Phosphorylation promotes complex formation indirectly, possibly by inducing a conformational change in full-length separase. (PMID:17974570)
• The complete removal of cohesin from chromosome arms depends on separase. (PMID:18003702)
• Separase has targets involved in regulation of G(2) to M progression after DNA damage in lung cancer cells. (PMID:18616699)
• These results collectively suggest that Separase is an oncogene, whose overexpression alone in mammary epithelial cells is sufficient to induce aneuploidy and tumorigenesis in a p53 mutant background. (PMID:18728194)
• Aurora B kinase activity helps coordinate the association of separase with chromosome and the initiation of sister-chromatid separation. (PMID:19342897)
• Study reports that cohesin cleavage by human separase requires DNA in a sequence-nonspecific manner. (PMID:19345191)
• Separase might be an oncogene, whose overexpression induces tumorigenesis. Separase overexpression and aberrant nuclear localization are common in many tumor types and may predict outcome in some human cancers. (PMID:19351757)
• Plk1 and separase act at different times during M phase to license centrosome duplication, reminiscent of their roles in removing cohesin from chromosomes (PMID:19758559)
• Plk1-mediated phosphorylation of Cdc6 promotes the interaction of Cdc6 and Cdk1, leading to the attenuation of Cdk1 activity, release of separase, and subsequent anaphase progression. (PMID:21041660)
• SMC3 and separase are upregulated and securin is downregulated in malignant transformation of BEAS-2B cells induced by coal tar pitch smoke extracts. (PMID:21126432)
• Results identify a new functional role of securin and separase in the modulation of membrane traffic and protein secretion that implicates regulation of V-ATPase assembly and function. (PMID:21272169)
• Kendrin is a novel and crucial substrate for separase (ESPL1) at the centrosome, protecting the engaged centrioles from premature disengagement and thereby blocking reduplication until the cell passes through mitosis. (PMID:22542101)
• By consecutively acting as a protease and a cdk1 inhibitor, separase coordinates two key processes to achieve simultaneous and abrupt separation of sister chromatids. (PMID:22814604)
• Mutation of the homologous position in PTTG1 (H(134)) switched PTTG1 from an inhibitor into an activator of ESP1. (PMID:23798554)
• Separase is an oncogene whose overexpression induces tumorigenesis, and indicate that Separase overexpression and aberrant nuclear localization are common in many tumor types and may predict outcome in some human malignancies. (PMID:24792645)
• High ESPL1 mRNA expression was associated with luminal B breast cancers. (PMID:25086634)
• Recruitment and activation of separase at centrosomes are two distinct steps that do not require microtubules. (PMID:25299182)
• Data indicate that separase is subject to native-state cis/trans isomerization by peptidyl-prolyl-isomerase Pin1. (PMID:25921067)
• Separase protein levels decrease and Separase proteolytic activity increases exclusively in b3a2 p210BCR-ABL-positive cell lines under Imatinib treatment. (PMID:26087013)
• The assay was used to quantify Separase proteolytic activity in leukemic cell lines and peripheral blood samples from leukemia patients. (PMID:26267133)
• Proximity mapping of human separase has been presented. (PMID:27495871)
• Studies identified and characterized the role of separase in mitosis, meiosis, non-canonical roles, its regulation, as a regulator of centriole disengagement, non proteolytic roles, diverse substrates, structural insights, and association of separase with cancer. [review] (PMID:27966791)
• High ESP expression is associated with breast cancer. (PMID:28859055)
• Separase activity measurement may therefore be useful as a novel additional molecular marker for disease monitoring (PMID:29370237)
• Thus, tethering of separase to DSBs and confined cohesin cleavage promote DSB repair in G2 cells. Importantly, this conserved interphase function of separase protects mammalian cells from oncogenic transformation. (PMID:30305303)
• LPE motif on the Scc1 substrate is required for rapid and specific cleavage by separase. (PMID:31729382)
• data suggests an association between high separase activity, residual BCR-ABL1 gene expression, and enhanced proliferative capacity in hematopoietic cells within the leukemic niche of TKI-treated chronic phase CML. (PMID:32253454)
• human cells that enter mitosis with already active separase rapidly undergo death in mitosis owing to direct cleavage of anti-apoptotic MCL1 and BCL-XL by separase; separase-triggered apoptosis enforces minimal length of mitosis (PMID:32322059)
• results identify an unexpected function of SGO2 in mitotically dividing cells and a mechanism of separase regulation that is independent of securin but still supervised by the spindle assembly checkpoint (PMID:32322060)
• Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants. (PMID:32574725)
• TTK, CDC25A, and ESPL1 as Prognostic Biomarkers for Endometrial Cancer. (PMID:33282948)
• Serum ESPL1 Can Be Used as a Biomarker for Patients With Hepatitis B Virus-Related Liver Cancer: A Chinese Case-Control Study. (PMID:33308056)
• [Separase, a key-player of mitosis: A new target for cancer therapy?]", trans “La separase, proteine-cle de la mitose - Une nouvelle cible therapeutique anti-cancereuse ? (PMID:34180834)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	espl1	ENSDARG00000075354
mus_musculus	Espl1	ENSMUSG00000058290
rattus_norvegicus	Espl1	ENSRNOG00000012835
drosophila_melanogaster	Sse	FBGN0035627
caenorhabditis_elegans	sep-1	WBGENE00004775
caenorhabditis_elegans		WBGENE00022741

Protein

Protein identifiers

Separin — Q14674 (reviewed: Q14674)

Alternative names: Caspase-like protein ESPL1, Extra spindle poles-like 1 protein, Separase

All UniProt accessions (3): Q14674, H3BM31, H3BRX7

UniProt curated annotations — full annotation on UniProt →

Function. Caspase-like protease, which plays a central role in the chromosome segregation by cleaving the SCC1/RAD21 subunit of the cohesin complex at the onset of anaphase. During most of the cell cycle, it is inactivated by different mechanisms.

Subunit / interactions. Interacts with PTTG1. Interacts with RAD21.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Autocleaves. This function, which is not essential for its protease activity, is unknown. Phosphorylated by CDK1. There are 8 Ser/Thr phosphorylation sites. Among them, Ser-1126 phosphorylation is the major site, which conducts to the enzyme inactivation.

Activity regulation. Regulated by at least two independent mechanisms. First, it is inactivated via its interaction with securin/PTTG1, which probably covers its active site. The association with PTTG1 is not only inhibitory, since PTTG1 is also required for activating it, the enzyme being inactive in cells in which PTTG1 is absent. PTTG1 degradation at anaphase, liberates it and triggers RAD21 cleavage. Second, phosphorylation at Ser-1126 inactivates it. The complete phosphorylation during mitosis, is removed when cells undergo anaphase. Activation of the enzyme at the metaphase-anaphase transition probably requires the removal of both securin and inhibitory phosphate.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14674-1	1	yes
Q14674-2	2

RefSeq proteins (1): NP_036423* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005314	Peptidase_C50	Family
IPR030397	SEPARIN_core_dom	Domain

Pfam: PF03568

Enzyme classification (BRENDA):

• EC 3.4.22.49 — separase (BRENDA: 22 organisms, 108 substrates, 86 inhibitors, 1 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-ASP-ARG-GLU-ILE-NLE-ARG-7-AMIDO-4-METHYLC	0.293	1

UniProt features (148 total): helix 69, strand 27, turn 15, mutagenesis site 8, sequence variant 6, sequence conflict 6, modified residue 4, compositionally biased region 4, region of interest 3, site 2, chain 1, domain 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
9HN0	ELECTRON MICROSCOPY	2.8
7NJ1	ELECTRON MICROSCOPY	2.9
9HN4	ELECTRON MICROSCOPY	2.93
9HN5	ELECTRON MICROSCOPY	2.96
9HM7	ELECTRON MICROSCOPY	3.1
9HMA	ELECTRON MICROSCOPY	3.3
9HMS	ELECTRON MICROSCOPY	3.4
9HVY	ELECTRON MICROSCOPY	3.5
7NJ0	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14674-F1	75.67	0.27

Functional residue map

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

Catalytic / active sites (3): 1506–1507 (cleavage; by autolysis); 1535–1536 (cleavage; by autolysis); 2029

Post-translational modifications (4): 1126, 1396, 1399, 1508

Mutagenesis-validated functional residues (8):

Position	Phenotype
1126	abolishes phosphorylation at this site, as well as the negative regulation due to phosphorylation.
1483–1486	abolishes autocleavage; when associated with r-1178; e-1181; r-1207 and e-1210. does not affect the protease function.
1486	abolishes autocleavage; when associated with a-1181 and a-1210.
1503–1506	does not affect autocleavage. does not affect the protease function.
1506	abolishes autocleavage; when associated with a-1161 and a-1210.
1532–1535	strongly reduces autocleavage at this site, but enhances autocleavage at site 1. does not affect the protease function.
1535	abolishes autocleavage; when associated with a-1161 and a-1281.
2029	abolishes protease activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2467813	Separation of Sister Chromatids

MSigDB gene sets: 323 (showing top): GNF2_CKS1B, GOBP_MITOTIC_CYTOKINESIS, GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, MORF_DNMT1, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, MODULE_52, RRAGTTGT_UNKNOWN, HORIUCHI_WTAP_TARGETS_DN, MORF_ESPL1, MORF_BUB1, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_SPINDLE_LOCALIZATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, MORF_RRM1

GO Biological Process (16): mitotic sister chromatid segregation (GO:0000070), meiotic spindle organization (GO:0000212), mitotic cytokinesis (GO:0000281), proteolysis (GO:0006508), apoptotic process (GO:0006915), establishment of mitotic spindle localization (GO:0040001), homologous chromosome segregation (GO:0045143), positive regulation of mitotic metaphase/anaphase transition (GO:0045842), negative regulation of sister chromatid cohesion (GO:0045875), mitotic sister chromatid separation (GO:0051306), meiotic chromosome separation (GO:0051307), mitotic cell cycle (GO:0000278), nuclear division (GO:0000280), chromosome segregation (GO:0007059), meiosis I (GO:0007127), nuclear chromosome segregation (GO:0098813)

GO Molecular Function (6): catalytic activity (GO:0003824), cysteine-type endopeptidase activity (GO:0004197), cysteine-type peptidase activity (GO:0008234), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), mitotic spindle (GO:0072686)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Mitotic Anaphase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitotic cell cycle process	3
mitotic nuclear division	2
meiotic cell cycle	2
meiotic cell cycle process	2
mitotic cell cycle	2
meiotic chromosome segregation	2
chromosome separation	2
cellular anatomical structure	2
sister chromatid segregation	1
spindle organization	1
cytoskeleton-dependent cytokinesis	1
protein metabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
establishment of spindle localization	1
microtubule cytoskeleton organization involved in mitosis	1
meiosis I	1
metaphase/anaphase transition of mitotic cell cycle	1
regulation of mitotic metaphase/anaphase transition	1
positive regulation of mitotic nuclear division	1
positive regulation of mitotic sister chromatid separation	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of metaphase/anaphase transition of cell cycle	1
sister chromatid cohesion	1
regulation of sister chromatid cohesion	1
negative regulation of cell cycle process	1
negative regulation of chromosome organization	1
mitotic sister chromatid segregation	1
cell cycle	1
organelle fission	1
cell cycle process	1
meiotic telophase I	1
meiosis I cell cycle process	1
meiotic nuclear division	1
chromosome segregation	1
molecular_function	1
endopeptidase activity	1
cysteine-type peptidase activity	1
peptidase activity	1

Protein interactions and networks

STRING

2801 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ESPL1	PTTG1	O95997	999
ESPL1	PTTG2	Q9NZH5	999
ESPL1	RAD21	O60216	953
ESPL1	SMC3	Q9UQE7	942
ESPL1	CDC14A	Q9UNH5	941
ESPL1	AURKB	Q96GD4	933
ESPL1	WAPL	Q7Z5K2	923
ESPL1	BUB1	O43683	919
ESPL1	CDC20	Q12834	918
ESPL1	CDK1	P06493	914
ESPL1	REC8	O95072	907
ESPL1	PDS5A	Q29RF7	898
ESPL1	STAG1	Q8WVM7	896
ESPL1	SGO1	Q5FBB7	894
ESPL1	CCNB1	P14635	877

IntAct

68 interactions, top by confidence:

A	B	Type	Score
ESPL1	PTTG1	psi-mi:“MI:0407”(direct interaction)	0.900
PTTG1	ESPL1	psi-mi:“MI:0914”(association)	0.900
PTTG1	ESPL1	psi-mi:“MI:0407”(direct interaction)	0.900
ESPL1	PTTG1	psi-mi:“MI:0914”(association)	0.900
ESPL1	PTTG1	psi-mi:“MI:0915”(physical association)	0.900
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
ESPL1	RAD21	psi-mi:“MI:0407”(direct interaction)	0.620
RAD21	ESPL1	psi-mi:“MI:0570”(protein cleavage)	0.620
ESPL1	RAD21	psi-mi:“MI:0570”(protein cleavage)	0.620
Espl1	PTTG1	psi-mi:“MI:0915”(physical association)	0.560
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
IARS2	GAK	psi-mi:“MI:0914”(association)	0.530
GFOD1	PER1	psi-mi:“MI:0914”(association)	0.530
FBXO4	AMD1	psi-mi:“MI:0914”(association)	0.530
Cdk1	PHGDH	psi-mi:“MI:0914”(association)	0.500
CCNB1	PTTG1	psi-mi:“MI:0915”(physical association)	0.490
ESPL1	CCT7	psi-mi:“MI:0915”(physical association)	0.400
ESPL1	HDAC2	psi-mi:“MI:0915”(physical association)	0.400
PTTG1	PTTG1	psi-mi:“MI:0915”(physical association)	0.400
Cdk1		psi-mi:“MI:0915”(physical association)	0.400
KIF2C	WDR62	psi-mi:“MI:0914”(association)	0.350
PTTG1	PMS1	psi-mi:“MI:0914”(association)	0.350
Ncaph	ATP5MF-PTCD1	psi-mi:“MI:0914”(association)	0.350
TTK	IBTK	psi-mi:“MI:0914”(association)	0.350

BioGRID (132): ESPL1 (Affinity Capture-RNA), ESPL1 (Affinity Capture-RNA), ESPL1 (Affinity Capture-MS), ESPL1 (Affinity Capture-MS), ESPL1 (Affinity Capture-MS), ESPL1 (Affinity Capture-MS), ESPL1 (Affinity Capture-MS), ESPL1 (Affinity Capture-MS), ESPL1 (Affinity Capture-MS), ESPL1 (Affinity Capture-MS), ESPL1 (Affinity Capture-MS), ESPL1 (Affinity Capture-MS), ESPL1 (Affinity Capture-MS), ESPL1 (Affinity Capture-MS), ESPL1 (Affinity Capture-MS)

ESM2 similar proteins: A0JN53, A6NE52, A7E3N7, A8MYJ7, D3ZVB0, D4A615, E1BD59, G3MZC5, O15287, O43299, O75064, O94812, P58660, P60330, Q0P5G1, Q14674, Q1JPD6, Q2VPB7, Q3HNM7, Q3TAP4, Q3U829, Q58EX7, Q5BK61, Q6DT37, Q6NZL6, Q6ZNJ1, Q6ZQA0, Q76MJ5, Q7Z614, Q80TE0, Q80TT2, Q80UW5, Q80VA5, Q8BGI5, Q8BUI3, Q8BYG0, Q8C0Q3, Q8C159, Q8C3R1, Q8CIE4

Diamond homologs: P18296, P33144, P60330, Q03018, Q14674, Q5IBC5

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CDK1	down-regulates	ESPL1	phosphorylation
MAPK1	down-regulates	ESPL1	phosphorylation
ESPL1	“down-regulates quantity by destabilization”	RAD21	cleavage
PTTG1	“down-regulates activity”	ESPL1	binding
PLK1	“down-regulates activity”	ESPL1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	194
Likely benign	32
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

4741 predictions. Top by Δscore:

Variant	Effect	Δscore
12:53268924:GA:G	donor_gain	1.0000
12:53268925:A:G	donor_gain	1.0000
12:53268929:G:GG	donor_gain	1.0000
12:53270673:TTCA:T	acceptor_loss	1.0000
12:53270675:CA:C	acceptor_loss	1.0000
12:53270676:A:AG	acceptor_gain	1.0000
12:53270677:G:GC	acceptor_gain	1.0000
12:53270677:GATA:G	acceptor_gain	1.0000
12:53270799:G:GG	donor_gain	1.0000
12:53276856:ACTG:A	donor_gain	1.0000
12:53276859:GGTA:G	donor_loss	1.0000
12:53276860:G:GG	donor_gain	1.0000
12:53276861:T:G	donor_loss	1.0000
12:53277081:A:AG	acceptor_gain	1.0000
12:53277082:G:GA	acceptor_gain	1.0000
12:53277082:GC:G	acceptor_gain	1.0000
12:53277082:GCTCT:G	acceptor_gain	1.0000
12:53277210:G:GT	donor_gain	1.0000
12:53277224:GGAA:G	donor_gain	1.0000
12:53277225:G:T	donor_gain	1.0000
12:53277225:GAA:G	donor_gain	1.0000
12:53277225:GAAG:G	donor_gain	1.0000
12:53277228:G:GG	donor_gain	1.0000
12:53277468:AG:A	acceptor_gain	1.0000
12:53277469:GG:G	acceptor_gain	1.0000
12:53277557:G:GT	donor_gain	1.0000
12:53277558:A:T	donor_gain	1.0000
12:53277576:G:GG	donor_gain	1.0000
12:53277810:T:TA	acceptor_gain	1.0000
12:53277811:G:A	acceptor_gain	1.0000

AlphaMissense

13612 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:53292002:T:A	W1904R	0.998
12:53292002:T:C	W1904R	0.998
12:53293295:T:A	W2062R	0.998
12:53293295:T:C	W2062R	0.998
12:53283402:T:A	W981R	0.996
12:53283402:T:C	W981R	0.996
12:53292333:T:A	V1951D	0.996
12:53292900:A:C	S2031R	0.996
12:53292902:T:A	S2031R	0.996
12:53292902:T:G	S2031R	0.996
12:53293297:G:C	W2062C	0.996
12:53293297:G:T	W2062C	0.996
12:53293349:T:A	W2080R	0.996
12:53293349:T:C	W2080R	0.996
12:53292653:T:G	Y1998D	0.995
12:53292818:T:A	H2003Q	0.995
12:53292818:T:G	H2003Q	0.995
12:53290433:G:C	W1776C	0.994
12:53290433:G:T	W1776C	0.994
12:53292329:T:G	Y1950D	0.994
12:53292336:T:C	L1952P	0.994
12:53292584:T:A	W1975R	0.994
12:53292584:T:C	W1975R	0.994
12:53293293:T:C	L2061P	0.994
12:53293323:G:C	R2071P	0.994
12:53293430:G:T	G2107W	0.994
12:53290444:G:C	R1780P	0.993
12:53292813:G:T	G2002W	0.993
12:53292814:G:A	G2002E	0.993
12:53292969:T:C	C2054R	0.993

dbSNP variants (sampled 300 via entrez): RS1000195721 (12:53284568 T>A), RS1000497413 (12:53280684 A>T), RS1000603702 (12:53270680 A>G), RS1000846742 (12:53272997 C>A,T), RS1001222869 (12:53274009 C>G), RS1001362664 (12:53280506 C>T), RS1001373972 (12:53280269 C>T), RS1001472049 (12:53287357 G>A,T), RS1001569307 (12:53274224 A>T), RS1001729475 (12:53266554 G>A), RS1001736176 (12:53287161 C>T), RS1001780068 (12:53266417 G>A), RS1001884322 (12:53285789 C>T), RS1001886505 (12:53293652 A>T), RS1001979872 (12:53293267 T>A)

Disease associations

OMIM: gene MIM:604143 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005795_35	Femoral neck bone mineral density	2.000000e-06
GCST005796_21	Lumbar spine bone mineral density	3.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007785	femoral neck bone mineral density
EFO:0007701	spine bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523294 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, increases expression	5
bisphenol A	affects cotreatment, increases methylation, increases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Fulvestrant	affects cotreatment, increases methylation, decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Estradiol	increases expression	2
Tetrachlorodibenzodioxin	affects expression, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
FR900359	decreases phosphorylation	1
echimidine	decreases expression, increases metabolic processing	1
dicrotophos	increases expression	1
lasiocarpine	decreases expression, increases metabolic processing	1
methyleugenol	decreases expression	1
propionaldehyde	decreases expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
geraniol	decreases expression	1
riddelliine	decreases expression, increases metabolic processing	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
diallyl trisulfide	decreases expression	1
phenethyl isothiocyanate	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4432629	Binding	Inhibition of epitope-tagged separase (unknown origin) using Rad21-MCA as substrate preincubated for 1 hr followed by substrate addition measured after 3 hrs by fluorescence assay	Synthesis and activity of benzimidazole-1,3-dioxide inhibitors of separase. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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