ANKLE1

Summary

ANKLE1 (ankyrin repeat and LEM domain containing 1, HGNC:26812) is a protein-coding gene on chromosome 19p13.11, encoding Structure-specific endonuclease ANKLE1 (Q8NAG6). Structure-selective DNA endonuclease that specifically cleaves branched DNA.

Enables endonuclease activity. Involved in DNA damage response and protein export from nucleus. Located in cytosol and nucleoplasm.

Source: NCBI Gene 126549 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 132 total
• MANE Select transcript: NM_152363

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26812
Approved symbol	ANKLE1
Name	ankyrin repeat and LEM domain containing 1
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	FLJ39369, LEMD6
Ensembl gene	ENSG00000160117
Ensembl biotype	protein_coding
OMIM	619348
Entrez	126549

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 7 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000394458, ENST00000404085, ENST00000404261, ENST00000594072, ENST00000596099, ENST00000596626, ENST00000596834, ENST00000598347, ENST00000601401, ENST00000651416, ENST00000652132, ENST00000935386, ENST00000935387

RefSeq mRNA: 4 — MANE Select: NM_152363 NM_001278443, NM_001278444, NM_001278445, NM_152363

CCDS: CCDS12354, CCDS92554

Canonical transcript exons

ENST00000404085 — 9 exons

Exon	Start	End
ENSE00003462974	17282057	17282209
ENSE00003567096	17284089	17284266
ENSE00003569839	17285681	17285819
ENSE00003589268	17282656	17282761
ENSE00003653674	17283225	17283962
ENSE00003680932	17285431	17285590
ENSE00003713755	17282864	17283002
ENSE00003716386	17286380	17287646
ENSE00003894930	17281901	17281982

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 75.94.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4767 / max 198.7961, expressed in 346 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174481	0.9234	278
174478	0.2116	68
174482	0.1210	62
174480	0.0990	15
174477	0.0939	46
174479	0.0278	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.94	silver quality
bone marrow	UBERON:0002371	75.59	gold quality
bone marrow cell	CL:0002092	73.95	gold quality
cerebellar hemisphere	UBERON:0002245	73.55	gold quality
right hemisphere of cerebellum	UBERON:0014890	73.55	gold quality
cerebellar cortex	UBERON:0002129	73.47	gold quality
granulocyte	CL:0000094	73.34	gold quality
trabecular bone tissue	UBERON:0002483	73.24	gold quality
monocyte	CL:0000576	71.74	gold quality
cerebellum	UBERON:0002037	71.55	gold quality
leukocyte	CL:0000738	71.44	gold quality
stromal cell of endometrium	CL:0002255	68.27	gold quality
tendon of biceps brachii	UBERON:0008188	66.89	gold quality
spleen	UBERON:0002106	66.85	gold quality
lymph node	UBERON:0000029	66.71	gold quality
ventricular zone	UBERON:0003053	66.09	gold quality
vermiform appendix	UBERON:0001154	65.61	gold quality
ganglionic eminence	UBERON:0004023	65.35	gold quality
lower esophagus mucosa	UBERON:0035834	64.29	gold quality
cortical plate	UBERON:0005343	63.48	gold quality
mucosa of stomach	UBERON:0001199	62.49	gold quality
right ovary	UBERON:0002118	62.20	gold quality
blood	UBERON:0000178	62.02	gold quality
right frontal lobe	UBERON:0002810	61.53	gold quality
left ovary	UBERON:0002119	61.09	gold quality
medial globus pallidus	UBERON:0002477	60.19	silver quality
caecum	UBERON:0001153	60.10	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	59.83	gold quality
lower esophagus	UBERON:0013473	59.57	gold quality
lower esophagus muscularis layer	UBERON:0035833	59.55	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.27

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

30 targeting ANKLE1, 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-8485	100.00	77.57	4731
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-12135	98.99	70.26	1814
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-6769A-5P	97.99	64.16	851
HSA-MIR-3159	97.94	66.79	1098
HSA-MIR-6502-3P	97.86	65.43	569
HSA-MIR-3909	97.55	66.78	887
HSA-MIR-5685	97.02	64.34	1004
HSA-MIR-4690-3P	97.02	64.72	981
HSA-MIR-656-5P	96.82	67.67	372
HSA-MIR-1182	96.41	64.89	336
HSA-MIR-4509	96.19	65.80	900
HSA-MIR-584-5P	95.82	68.05	848
HSA-MIR-5681B	94.82	69.30	514

Literature-anchored findings (GeneRIF, showing 10)

• Ankle1 is conserved in metazoans and contains a unique C-terminal GIY-YIG motif that confers endonuclease activity in vitro and in vivo (PMID:22399800)
• the domains mediating nuclear import and export of Ankle1, were identified. (PMID:27245214)
• Expression of RCCD1 in whole blood was also suggestively associated with disease risk (p-value: 1.2x10-05), as were expression of ACAP1 (p-value: 1.9x10-05) and LRRC25 (p-value: 5.2x10-05). While genome-wide association studies (GWAS) have implicated RCCD1 and ANKLE1 in breast cancer risk, they have not identified the remaining three genes (PMID:28362817)
• We used The Cancer Genome Atlas breast cancer patient data to identify ANKLE1 and ZNF404 as the target genes of candidate TF binding site SNPs in the 19p13.11 and 19q13.31 GWAS-identified loci. These SNPs are associated with the expression of ZNF404 and ANKLE1 in breast tissue. (PMID:28957321)
• ANKLE1 N(6) -Methyladenosine-related variant is associated with colorectal cancer risk by maintaining the genomic stability. (PMID:31509622)
• Human ANKLE1 Is a Nuclease Specific for Branched DNA. (PMID:32866453)
• Investigation of triple-negative breast cancer risk alleles in an International African-enriched cohort. (PMID:33927264)
• Human Endonuclease ANKLE1 Localizes at the Midbody and Processes Chromatin Bridges to Prevent DNA Damage and cGAS-STING Activation. (PMID:36825683)
• Dephosphocholination by Legionella effector Lem3 functions through remodelling of the switch II region of Rab1b. (PMID:37076474)
• Biochemical and mechanistic analysis of the cleavage of branched DNA by human ANKLE1. (PMID:37216589)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:85936	ENSDARG00000087529
mus_musculus	Ankle1	ENSMUSG00000046295
rattus_norvegicus	Ankle1	ENSRNOG00000017156

Paralogs (2): LEMD2 (ENSG00000161904), LEMD3 (ENSG00000174106)

Protein

Protein identifiers

Structure-specific endonuclease ANKLE1 — Q8NAG6 (reviewed: Q8NAG6)

Alternative names: Ankyrin repeat and LEM domain-containing protein 1, Ankyrin repeat domain-containing protein 41, LEM-domain containing protein 3

All UniProt accessions (6): Q8NAG6, A0A0A0MSC6, A0A494C092, A0A499FJM0, M0QX15, M0R002

UniProt curated annotations — full annotation on UniProt →

Function. Structure-selective DNA endonuclease that specifically cleaves branched DNA. Processes chromatin bridges during cytokinesis by cleaving DNA, both priming TREX1-mediated resolution and directly resolving bridges. Proper processing of chromatin bridges prevents their breakage during cytokinesis, thereby reducing DNA damage, micronuclei formation, and the activation of immune responses such as the cGAS-STING pathway.

Subunit / interactions. Monomer. Interacts (via LEM domain) with BANF1; the interaction may favor BANF1 dimerization.

Subcellular location. Cytoplasm. Nucleus. Midbody.

Tissue specificity. Expression is predominant in adult bone marrow.

Domain organisation. The LEM domain is required for GIY-YIG domain-mediated DNA cleavage and induction of DNA damage response. The GIY-YIG domain is required for nuclease cleavage close to DNA branchpoints. The ANK repeats are essential for its localization to the midbody.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NAG6-2	1	yes
Q8NAG6-1	2

RefSeq proteins (4): NP_001265372, NP_001265373, NP_001265374, NP_689576* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000305	GIY-YIG_endonuc	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR003887	LEM_dom	Domain
IPR011015	LEM/LEM-like_dom_sf	Homologous_superfamily
IPR034998	ANKLE1	Family
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF12796, PF22945

UniProt features (33 total): mutagenesis site 11, sequence variant 8, repeat 3, splice variant 2, domain 2, region of interest 2, short sequence motif 2, chain 1, compositionally biased region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NAG6-F1	70.14	0.40

Functional residue map

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

Mutagenesis-validated functional residues (11):

Position	Phenotype
110–117	slight increase in nuclear localization.
271–280	increased nuclear localization.
453	loss of endonucleolytic activity.
486–488	probable loss of endonucleolytic activity. fails to induce dna damage response upon leptomycin-mediated nuclear localiza
486	loss of endonucleolytic activity.
488	loss of endonucleolytic activity.
498	reduced endonucleolytic activity.
519	reduced endonucleolytic activity.
551	loss of endonucleolytic activity.
565	loss of endonucleolytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 101 (showing top): GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOMF_ENDONUCLEASE_ACTIVITY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOMF_NUCLEASE_ACTIVITY, GOBP_NEGATIVE_REGULATION_OF_DNA_RECOMBINATION, GOBP_NUCLEAR_TRANSPORT, GOBP_ORGANELLE_FISSION, TGCTGAY_UNKNOWN, GOBP_DNA_DAMAGE_RESPONSE, GOBP_REGULATION_OF_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_MITOTIC_RECOMBINATION, GOBP_MEIOTIC_CELL_CYCLE_PROCESS, GOBP_NUCLEAR_EXPORT, GOBP_RECOMBINATIONAL_REPAIR

GO Biological Process (9): resolution of meiotic recombination intermediates (GO:0000712), double-strand break repair via homologous recombination (GO:0000724), protein export from nucleus (GO:0006611), DNA damage response (GO:0006974), negative regulation of mitotic recombination (GO:0045950), nucleic acid metabolic process (GO:0090304), regulation of myeloid progenitor cell differentiation (GO:1905453), regulation of lymphoid progenitor cell differentiation (GO:1905456), DNA repair (GO:0006281)

GO Molecular Function (8): magnesium ion binding (GO:0000287), endonuclease activity (GO:0004519), DNA endonuclease activity (GO:0004520), hydrolase activity (GO:0016787), manganese ion binding (GO:0030145), cobalt ion binding (GO:0050897), nuclease activity (GO:0004518), protein binding (GO:0005515)

GO Cellular Component (6): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), midbody (GO:0030496), nucleus (GO:0005634), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
regulation of hematopoietic progenitor cell differentiation	2
transition metal ion binding	2
reciprocal meiotic recombination	1
meiosis I cell cycle process	1
recombinational repair	1
double-strand break repair	1
intracellular protein transport	1
nuclear export	1
cellular response to stress	1
regulation of mitotic recombination	1
mitotic recombination	1
negative regulation of DNA recombination	1
nucleobase-containing compound metabolic process	1
macromolecule metabolic process	1
myeloid progenitor cell differentiation	1
lymphoid progenitor cell differentiation	1
DNA metabolic process	1
DNA damage response	1
metal ion binding	1
nuclease activity	1
endonuclease activity	1
DNA nuclease activity	1
catalytic activity	1
catalytic activity, acting on a nucleic acid	1
binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1176 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANKLE1	ABHD8	Q96I13	718
ANKLE1	ANKLE2	Q86XL3	700
ANKLE1	LEMD2	Q8NC56	626
ANKLE1	BABAM1	Q9NWV8	622
ANKLE1	DVL1	O14640	613
ANKLE1	RAB1A	P11476	605
ANKLE1	LEMD3	Q9Y2U8	601
ANKLE1	BANF1	O75531	575
ANKLE1	CIMAP2	Q3ZCV2	567
ANKLE1	EMD	P50402	528
ANKLE1	SLX1A	Q9BQ83	510
ANKLE1	BANF2	Q9H503	487
ANKLE1	ERI1	Q8IV48	474
ANKLE1	CDC50B	Q3MIR4	473
ANKLE1	LEMD1	Q68G75	445

IntAct

1 interactions, top by confidence:

BioGRID (5): ANKLE1 (Negative Genetic), ANKLE1 (Positive Genetic), ANKLE1 (Affinity Capture-RNA), ANKLE1 (Affinity Capture-MS), ANKLE1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A0J9YX94, A0A0J9YXQ4, A0A0J9YY54, A0A494C1R9, A1L443, A5D7L8, A6NDY0, A6NKD2, E9PGG2, F6SZT2, O19110, O75807, O88852, P0CV98, P0CV99, P0CW00, P0CW01, P0CW24, P0DV79, P17564, P59644, P78358, Q01534, Q0P5N2, Q15735, Q2KI51, Q587J8, Q5R5G8, Q5R6R8, Q5RFC2, Q5SV97, Q60465, Q6P752, Q86V59, Q8BSI6, Q8N9W4, Q8NAG6, Q8NEE8, Q8VD63, Q95LS7

Diamond homologs: A8VU90, G5EGA3, Q8NAG6, Q05823, Q5VYY1, Q9D3J5, Q9FPH0, Q9J512

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	107
Likely benign	10
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

1511 predictions. Top by Δscore:

Variant	Effect	Δscore
19:17281972:G:GT	donor_gain	1.0000
19:17282205:GCTCG:G	donor_gain	1.0000
19:17282207:TCGG:T	donor_loss	1.0000
19:17282208:CGG:C	donor_loss	1.0000
19:17282209:GGT:G	donor_loss	1.0000
19:17282210:G:GG	donor_gain	1.0000
19:17282210:GTAA:G	donor_loss	1.0000
19:17282210:GTAAG:G	donor_loss	1.0000
19:17282211:T:A	donor_loss	1.0000
19:17282981:G:GT	donor_gain	1.0000
19:17282998:TGGCA:T	donor_gain	1.0000
19:17282999:GGCA:G	donor_gain	1.0000
19:17282999:GGCAG:G	donor_gain	1.0000
19:17283000:GCA:G	donor_gain	1.0000
19:17283000:GCAG:G	donor_gain	1.0000
19:17283001:CA:C	donor_gain	1.0000
19:17283001:CAGTG:C	donor_loss	1.0000
19:17283003:GTGA:G	donor_gain	1.0000
19:17283004:T:G	donor_loss	1.0000
19:17283005:GAGTA:G	donor_loss	1.0000
19:17283006:AGT:A	donor_loss	1.0000
19:17283007:G:GG	donor_gain	1.0000
19:17284210:G:GT	donor_gain	1.0000
19:17284227:TCGTG:T	donor_gain	1.0000
19:17284281:A:T	donor_gain	1.0000
19:17285524:G:T	donor_gain	1.0000
19:17285579:TC:T	donor_gain	1.0000
19:17285589:AG:A	donor_loss	1.0000
19:17285590:GGTGT:G	donor_loss	1.0000
19:17285591:G:GG	donor_loss	1.0000

AlphaMissense

3908 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:17284241:T:C	F451L	0.994
19:17284243:C:A	F451L	0.994
19:17284243:C:G	F451L	0.994
19:17285725:G:C	W527C	0.991
19:17285725:G:T	W527C	0.991
19:17285507:T:C	F485L	0.990
19:17285509:C:A	F485L	0.990
19:17285509:C:G	F485L	0.990
19:17285520:A:T	K489I	0.990
19:17285759:T:C	F539L	0.990
19:17285761:C:A	F539L	0.990
19:17285761:C:G	F539L	0.990
19:17285712:T:C	I523T	0.988
19:17285723:T:A	W527R	0.986
19:17285723:T:C	W527R	0.986
19:17284187:T:C	F433L	0.985
19:17284189:T:A	F433L	0.985
19:17284189:T:G	F433L	0.985
19:17286436:T:A	W578R	0.983
19:17286436:T:C	W578R	0.983
19:17282691:C:A	A84D	0.981
19:17284251:T:C	L454P	0.981
19:17282688:C:A	A83D	0.980
19:17286463:G:T	G587W	0.980
19:17285492:T:C	F480L	0.978
19:17285494:C:A	F480L	0.978
19:17285494:C:G	F480L	0.978
19:17285517:G:T	G488V	0.978
19:17285521:A:C	K489N	0.978
19:17285521:A:T	K489N	0.978

dbSNP variants (sampled 300 via entrez): RS1000116851 (19:17281438 C>T), RS1000797636 (19:17281804 C>G,T), RS1000890879 (19:17281967 G>A), RS1001120053 (19:17286852 C>G,T), RS1001679544 (19:17282592 C>A,T), RS1002016487 (19:17281580 T>A), RS1002727253 (19:17287872 C>G,T), RS1002780715 (19:17287490 T>C), RS1003632478 (19:17282781 G>A), RS1003682784 (19:17280329 C>G), RS1004481439 (19:17280857 A>AT), RS1005130315 (19:17284941 G>A), RS1005161374 (19:17284550 A>G,T), RS1006000570 (19:17287477 A>T), RS1006374329 (19:17281916 A>G,T)

Disease associations

OMIM: gene MIM:619348 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000800_2	Ovarian cancer	1.000000e-07
GCST000801_1	Breast cancer	2.000000e-09
GCST005075_8	Breast Cancer in BRCA1 mutation carriers	3.000000e-17
GCST005076_10	Breast cancer (estrogen-receptor negative)	3.000000e-37
GCST007394_2	Mitochondrial DNA copy number	1.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006312	mitochondrial DNA measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	increases expression, increases methylation	2
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
arsenite	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
bisphenol S	increases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Copper	affects cotreatment, decreases expression	1
Diazinon	decreases methylation	1
Particulate Matter	increases expression, increases abundance	1

Clinical trials (associated diseases)

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