MUS81

Summary

MUS81 (MUS81 structure-specific endonuclease subunit, HGNC:29814) is a protein-coding gene on chromosome 11q13, encoding Structure-specific endonuclease subunit MUS81 (Q96NY9). Catalytic subunit of two functionally distinct, structure-specific, heterodimeric DNA endonucleases MUS81-EME1 and MUS81-EME2 that are involved in the maintenance of genome stability. It is a selective cancer dependency (DepMap: 16.0% of cell lines).

This gene encodes a structure-specific endonuclease which belongs to the XPF/MUS81 endonuclease family and plays a critical role in the resolution of recombination intermediates during DNA repair after inter-strand cross-links, replication fork collapse, and DNA double-strand breaks. The encoded protein associates with one of two closely related essential meiotic endonuclease proteins (EME1 or EME2) to form a complex that processes DNA secondary structures. It contains an N-terminal DEAH helicase domain, an excision repair cross complementation group 4 (ERCC4) endonuclease domain, and two tandem C-terminal helix-hairpin-helix domains. Mice with a homozygous knockout of the orthologous gene have significant meiotic defects including the failure to repair a subset of DNA double strand breaks.

Source: NCBI Gene 80198 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 140 total
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 16.0% of screened cell lines
• MANE Select transcript: NM_025128

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29814
Approved symbol	MUS81
Name	MUS81 structure-specific endonuclease subunit
Location	11q13
Locus type	gene with protein product
Status	Approved
Aliases	FLJ44872, SLX3
Ensembl gene	ENSG00000172732
Ensembl biotype	protein_coding
OMIM	606591
Entrez	80198

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 10 protein_coding, 7 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000308110, ENST00000524647, ENST00000525006, ENST00000525147, ENST00000525224, ENST00000525768, ENST00000529374, ENST00000529742, ENST00000529786, ENST00000529857, ENST00000530111, ENST00000530282, ENST00000530928, ENST00000531905, ENST00000533035, ENST00000533519, ENST00000533555, ENST00000907324, ENST00000971503, ENST00000971504

RefSeq mRNA: 2 — MANE Select: NM_025128 NM_001350283, NM_025128

CCDS: CCDS8115

Canonical transcript exons

ENST00000308110 — 16 exons

Exon	Start	End
ENSE00001231093	65863804	65863901
ENSE00001633025	65865017	65865145
ENSE00001764780	65861350	65861435
ENSE00002156991	65860433	65860888
ENSE00003458902	65863410	65863502
ENSE00003467886	65863600	65863721
ENSE00003489184	65864497	65864613
ENSE00003491043	65865220	65865323
ENSE00003502854	65861947	65862045
ENSE00003509263	65863065	65863205
ENSE00003543819	65864720	65864815
ENSE00003561423	65865986	65866439
ENSE00003595999	65862211	65862279
ENSE00003598709	65860973	65861102
ENSE00003641932	65865811	65865894
ENSE00003687298	65862444	65862529

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 96.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.5713 / max 200.2593, expressed in 1809 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
115221	6.8942	1675
115220	6.8701	1717
115219	2.0965	852
115225	1.6200	996
115226	0.9867	575
115223	0.9616	462
115222	0.6778	370
115224	0.2933	129
206342	0.1504	55
115228	0.0206	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of uterus	UBERON:0009853	96.87	gold quality
left uterine tube	UBERON:0001303	96.27	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.13	gold quality
granulocyte	CL:0000094	96.10	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.95	gold quality
mucosa of transverse colon	UBERON:0004991	95.84	gold quality
right ovary	UBERON:0002118	95.81	gold quality
endocervix	UBERON:0000458	95.74	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.72	gold quality
lower esophagus	UBERON:0013473	95.71	gold quality
right coronary artery	UBERON:0001625	95.63	gold quality
apex of heart	UBERON:0002098	95.57	gold quality
left coronary artery	UBERON:0001626	95.47	gold quality
left ovary	UBERON:0002119	95.46	gold quality
popliteal artery	UBERON:0002250	95.45	gold quality
tibial artery	UBERON:0007610	95.44	gold quality
ascending aorta	UBERON:0001496	95.39	gold quality
thoracic aorta	UBERON:0001515	95.34	gold quality
aorta	UBERON:0000947	95.33	gold quality
right lobe of thyroid gland	UBERON:0001119	95.28	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.19	gold quality
transverse colon	UBERON:0001157	95.14	gold quality
ectocervix	UBERON:0012249	95.10	gold quality
lower esophagus mucosa	UBERON:0035834	95.10	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.06	gold quality
left lobe of thyroid gland	UBERON:0001120	94.92	gold quality
tibial nerve	UBERON:0001323	94.88	gold quality
mucosa of stomach	UBERON:0001199	94.81	gold quality
spleen	UBERON:0002106	94.72	gold quality
coronary artery	UBERON:0001621	94.68	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

23 targeting MUS81, 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-4795-3P	100.00	74.62	4024
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-548D-3P	99.87	70.67	4362
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-646	99.68	67.84	1645
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-140-5P	99.44	67.20	792
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-4751	98.80	64.95	525
HSA-MIR-483-3P	97.77	64.95	731
HSA-MIR-647	97.73	67.79	927
HSA-MIR-376A-5P	97.70	65.61	863
HSA-MIR-1233-3P	96.81	65.44	573
HSA-MIR-3193	92.99	64.93	116

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 16.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Mus81-associated endonuclease may play a more direct role in replication fork collapse by catalysing the cleavage of stalled fork structures. (PMID:12374758)
• hMUS81.hMMS4 complex is a structure-specific nuclease that is capable of resolving fork structure [hMMS4] (PMID:12686547)
• Mus81 binds to a homolog of fission yeast Eme1 in vitro and in vivo and Mus81-Eme1 resolves Holliday junctions in vivo. (PMID:14617801)
• Mus81 is required to repair problems that arise most frequently in the highly repetitive nucleolar DNA. (PMID:14638871)
• Data suggest a new function of BLM in cooperating with Mus81 during processing and restoration of stalled replication forks. (PMID:15805243)
• Mus81 deficiency affects cell cycle progression and promotes DNA rereplication. (PMID:16456034)
• Pulsed-field gel electrophoresis of the mus81Delta mutant revealed an expansion of the rDNA locus depending on RAD52, in addition to fragmentation of Chr XII in the sgs1Deltamus81(ts) mutant at permissive temperature. (PMID:17555773)
• Mus81 and FANCB have different roles in repair of DNA damage during replication in human cells (PMID:17903171)
• Data suggest that Mus81 suppresses chromosomal instability by converting potentially detrimental replication-associated DNA structures into intermediates that are more amenable to DNA repair. (PMID:17934473)
• BLM helicase and Mus81 are required to induce transient double-stranded DNA breaks in response to DNA replication stress. (PMID:18054789)
• Mus81-Eme1 can ensure coordinate, bilateral cleavage of Holliday junction-like structures. (PMID:18310322)
• the crystal structure of the Mus81-Eme1 complex (PMID:18413719)
• Mutations and abnormal expression of MUS81 gene in the LSCC tissues were observed. (PMID:18841572)
• WRN is required to avoid accumulation of double-strand breaks and fork collapse after replication perturbation, and that prompt MUS81-dependent generation of DSBs is instrumental for recovery from hydroxyurea-mediated replication arrest. (PMID:18852298)
• results demonstrate a link between branch migration activity of hRad54 and structure-specific endonuclease activity of hMus81-Eme1, suggesting that the Rad54 and Mus81-Eme1 proteins may cooperate in the processing of Holliday junction-like intermediates (PMID:19017809)
• MUS81 is involved in the maintenance of ALT (alternative lengthening of telomeres) cell survival at least in part by homologous recombination of telomeres. (PMID:19363487)
• Mus81 is a novel prognostic marker for colorectal carcinoma (PMID:21175991)
• Mus81 down-regulation correlated significantly to invasion depth (p = 0.015) and poorly-differentiated type (p = 0.016) of gastric cancer. (PMID:21187482)
• Data show that Mus81/Eme1-dependent DNA damage–rather than a global increase in replication-fork stalling–is the cause of incomplete replication in Chk1-deficient cells. (PMID:21858151)
• Results demonstrate a novel role of Wee1 in controlling Mus81-Eme1 and DNA replication in human cells. (PMID:21859861)
• Mus81 cleaves stalled replication forks, which allows dissipation of the excessive supercoiling resulting from Top1 inhibition, spontaneous reversal of Top1cc, and replication fork progression. (PMID:22123861)
• we demonstrate that double-strand breaks, observed upon oncogene over-expression, depend on the MUS81 endonuclease, which represents a parallel pathway collaborating with WRN to prevent cell death. (PMID:22410776)
• FBH1 helicase activity is required to eliminate cells with excessive replication stress through the generation of MUS81-induced DNA double-strand breaks. (PMID:23361013)
• the DNA structure-specific nuclease MUS81-EME1 localizes to CFS loci in early mitotic cells, and promotes the cytological appearance of characteristic gaps or breaks observed at CFSs in metaphase chromosomes. (PMID:23811685)
• This study identified a winged helix domain within the N-terminal region of human MUS81 that binds DNA, increases the activity of MUS81-EME1/EME2 complexes and influences the incision position of MUS81-EME2 but not MUS81-EME1 complexes on synthetic forks, 3’ flaps and nicked Holliday junctions. (PMID:23982516)
• Data show that three structure-selective endonucleases, SLX1-SLX4, MUS81-EME1, and GEN1, define two pathways of Holliday junctions (HJs) resolution in HeLa cells. (PMID:24076221)
• In vivo HJ resolution depends on both SLX4-associated MUS81-EME1 and SLX1, suggesting that they are acting in concert in the context of SLX4. (PMID:24080495)
• Our findings reveal a novel RAD52/MUS81-dependent mechanism that promotes cell viability and genome integrity in checkpoint-deficient cells, and disclose the involvement of MUS81 to multiple processes after replication stress (PMID:24204313)
• The presence of a 5’ phosphate terminus at nicks and gaps rendered DNA significantly less susceptible to the cleavage by MUS81-EME2 than its absence. (PMID:24692662)
• While Mus81-Eme1 shares several common features with members of the 5’ flap nuclease family, the combined structural, biochemical, and biophysical analyses explain why Mus81-Eme1 preferentially cleaves 3’ flap DNA substrates with 5’ nicked ends. (PMID:24733841)
• Results define distinct and temporal roles for MUS81-EME1 and MUS81-EME2 in the maintenance of genome stability. (PMID:24813886)
• The data highlight the importance of Mus81 and Blm in DNA double-strand repair pathways, fertility, development and cancer. (PMID:24858046)
• Identification and characterization of MUS81 point mutations that abolish interaction with the SLX4 scaffold protein.MUS81 function in DNA interstrand crosslinks repair requires interaction with SLX4. (PMID:25224045)
• Authors confirmed that HIV-1 Vpr induces degradation of Mus81 although, surprisingly, degradation is independent and genetically separable from Vprs ability to induce G2 arrest. (PMID:25618414)
• Mus81 regulates the rate of DNA replication during normal growth by promoting replication fork progression while reducing the frequency of replication initiation events. (PMID:25879486)
• Mus81 knockdown improves the chemosensitivity of HCC cells by inducing S-phase arrest and promoting apoptosis through CHK1 pathway, suggesting Mus81 as a novel therapeutic target for HCC. (PMID:26714930)
• Avoiding damage formation through invalidation of Mus81-Eme2 and Mre11, or preventing damage signaling by turning off the ATM pathway, suppresses the replication phenotypes of Chk1-deficient cells. (PMID:26804904)
• down-regulation of MUS81 expression in ovarian cancer cells inhibited cell proliferation and colony formation ability, and influenced cell cycle progression (PMID:27255997)
• SLX4-SLX1 Protein-independent Down-regulation of MUS81-EME1 Protein by HIV-1 Viral Protein R (Vpr). (PMID:27354282)
• The mitotic DNA synthesis is RAD52 dependent, and RAD52 is required for the timely recruitment of MUS81 and POLD3 to common fragile sites in early mitosis. (PMID:27984745)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mus81	ENSDARG00000069326
mus_musculus	Mus81	ENSMUSG00000024906
rattus_norvegicus	Mus81	ENSRNOG00000020617
drosophila_melanogaster	mus81	FBGN0040347
caenorhabditis_elegans	mus-81	WBGENE00016602

Protein

Protein identifiers

Structure-specific endonuclease subunit MUS81 — Q96NY9 (reviewed: Q96NY9)

Alternative names: Crossover junction endonuclease MUS81, MUS81 endonuclease homolog

All UniProt accessions (8): E9PII7, E9PL60, E9PRI1, Q96NY9, H0YDE3, H0YDK3, H0YDU2, H0YE94

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of two functionally distinct, structure-specific, heterodimeric DNA endonucleases MUS81-EME1 and MUS81-EME2 that are involved in the maintenance of genome stability. Both endonucleases have essentially the same substrate specificity though MUS81-EME2 is more active than its MUS81-EME1 counterpart. Both cleave 3’-flaps and nicked Holliday junctions, and exhibit limited endonuclease activity with 5’ flaps and nicked double-stranded DNAs. MUS81-EME2 which is active during the replication of DNA is more specifically involved in replication fork processing. Replication forks frequently encounter obstacles to their passage, including DNA base lesions, DNA interstrand cross-links, difficult-to-replicate sequences, transcription bubbles, or tightly bound proteins. One mechanism for the restart of a stalled replication fork involves nucleolytic cleavage mediated by the MUS81-EME2 endonuclease. By acting upon the stalled fork, MUS81-EME2 generates a DNA double-strand break (DSB) that can be repaired by homologous recombination, leading to the restoration of an active fork. MUS81-EME2 could also function in telomere maintenance. MUS81-EME1, on the other hand, is active later in the cell cycle and functions in the resolution of mitotic recombination intermediates including the Holliday junctions, the four-way DNA intermediates that form during homologous recombination.

Subunit / interactions. Part of the heterodimeric DNA structure-specific endonuclease complex MUS81-EME1. Part of the heterodimeric DNA structure-specific endonuclease complex MUS81-EME2. Interacts with BLM; may stimulate the endonuclease activity of MUS81. Interacts with SLX4/BTBD12; this interaction is direct and links the MUS81-EME1 complex to SLX4, which may coordinate the action of the structure-specific endonuclease during DNA repair. Interacts with DCLRE1B/Apollo. Interacts with RECQL5; this interaction stimulates mitotic DNA synthesis. Interacts with CHEK2.

Subcellular location. Nucleus. Nucleolus.

Tissue specificity. Widely expressed.

Induction. Up-regulated in cells treated with agents that damage DNA or block replication. This up-regulation seems to be independent of transcription.

Similarity. Belongs to the XPF family.

RefSeq proteins (2): NP_001337212, NP_079404* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006166	ERCC4_domain	Domain
IPR010996	HHH_MUS81	Domain
IPR011335	Restrct_endonuc-II-like	Homologous_superfamily
IPR027421	DNA_pol_lamdba_lyase_dom_sf	Homologous_superfamily
IPR033309	Mus81	Family
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR042530	EME1/EME2_C	Homologous_superfamily
IPR047416	XPF_nuclease_Mus81	Domain
IPR047417	WHD_MUS81	Domain

Pfam: PF02732, PF14716, PF21136, PF21292

Enzyme classification (BRENDA):

• EC 3.1.21.10 — crossover junction endodeoxyribonuclease (BRENDA: 47 organisms, 156 substrates, 9 inhibitors, 10 Km, 22 kcat entries)

Substrate kinetics (BRENDA)

17 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3’-FLAPPED JUNCTION IN DNA	—	2
DNA JUNCTION 1	0.0001	2
D-LOOP JUNCTION IN DNA	—	1
INTACT HOLLIDAY JUNCTION	—	1
NXO12 JUNCTION IN SINGLE-STRANDED DNA	—	1
PXO12-3’ JUNCTION IN SINGLE-STRANDED DNA	—	1
REPLICATION FORK-LIKE JUNCTION IN DNA	—	1
SPLAYED Y JUNCTION IN DNA	—	1
DNA JUNCTION 1 UNCONSTRAINED	—	0
DNA JUNCTION J1T1	—	0
DNA JUNCTION J1T2	—	0
DNA JUNCTION RC1	—	0
DNA JUNCTION RC1(1,3')	—	0
DNA JUNCTION RC1(2,3')	—	0
HOLLIDAY JUNCTION 3 IN DNA	—	0

UniProt features (85 total): helix 22, mutagenesis site 17, strand 13, binding site 8, turn 7, sequence variant 6, region of interest 4, active site 3, modified residue 2, chain 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
7BU5	X-RAY DIFFRACTION	1.8
9F9L	X-RAY DIFFRACTION	2.02
9F98	X-RAY DIFFRACTION	2.15
9F9M	X-RAY DIFFRACTION	2.47
9F9K	X-RAY DIFFRACTION	2.73
4P0P	X-RAY DIFFRACTION	2.8
9F99	X-RAY DIFFRACTION	2.8
4P0Q	X-RAY DIFFRACTION	2.85
9F9A	X-RAY DIFFRACTION	2.91
7F6L	X-RAY DIFFRACTION	3.2
2ZIX	X-RAY DIFFRACTION	3.5
4P0S	X-RAY DIFFRACTION	6
4P0R	X-RAY DIFFRACTION	6.5
2MC3	SOLUTION NMR
6VWB	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96NY9-F1	79.46	0.44

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): 274; 277; 307

Ligand- & substrate-binding residues (8): 274; 277; 277; 307; 307; 333; 333; 334

Post-translational modifications (2): 95, 101

Mutagenesis-validated functional residues (17):

Position	Phenotype
186	reduced 5 prime flap and nhj cleavages but only mild effect on the cleavage of 3 prime flap; when associated with e-191.
191	reduced 5 prime flap and nhj cleavages but only mild effect on the cleavage of 3 prime flap; when associated with e-186.
274	loss of endonuclease activity.
277	loss of endonuclease activity.
306–307	loss of endonuclease activity.
307	loss of endonuclease activity.
333–334	loss of endonuclease activity.
338–339	loss of endonuclease activity.
344	decreased endonuclease activity; when associated r-345.
345	decreased endonuclease activity; when associated r-344.
348	reduced 3 prime flap and nhj cleavage and loss of 5 prime flap cleavage.
355	reduced 3 prime flap and nhj cleavage and loss of 5 prime flap cleavage.
383	decreased endonuclease activity; when associated with r-387.
387	decreased endonuclease activity; when associated with r-383.
483	loss of endonuclease activity; when associated with a-489 and a-530.
489	loss of endonuclease activity; when associated with a-483 and a-530.
530	decreased endonuclease activity. loss of endonuclease activity; when associated with a-483 and a-489.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-5693568	Resolution of D-loop Structures through Holliday Junction Intermediates
R-HSA-6783310	Fanconi Anemia Pathway
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5693532	DNA Double-Strand Break Repair
R-HSA-5693537	Resolution of D-Loop Structures
R-HSA-5693538	Homology Directed Repair
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)
R-HSA-73894	DNA Repair

MSigDB gene sets: 167 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_CHROMOSOME_ORGANIZATION, MODULE_97, GOMF_ENDONUCLEASE_ACTIVITY, WWTAAGGC_UNKNOWN, GOMF_NUCLEASE_ACTIVITY, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_TELOMERE_ORGANIZATION, MODULE_182, KAUFFMANN_DNA_REPAIR_GENES, chr11q13, KEGG_HOMOLOGOUS_RECOMBINATION

GO Biological Process (13): resolution of meiotic recombination intermediates (GO:0000712), telomere maintenance (GO:0000723), double-strand break repair via break-induced replication (GO:0000727), DNA repair (GO:0006281), double-strand break repair (GO:0006302), DNA catabolic process (GO:0006308), replication fork processing (GO:0031297), mitotic intra-S DNA damage checkpoint signaling (GO:0031573), osteoblast proliferation (GO:0033687), resolution of mitotic recombination intermediates (GO:0071140), response to intra-S DNA damage checkpoint signaling (GO:0072429), DNA recombination (GO:0006310), DNA damage response (GO:0006974)

GO Molecular Function (10): DNA binding (GO:0003677), endonuclease activity (GO:0004519), DNA endonuclease activity (GO:0004520), crossover junction DNA endonuclease activity (GO:0008821), metal ion binding (GO:0046872), 3’-flap endonuclease activity (GO:0048257), nuclease activity (GO:0004518), protein binding (GO:0005515), hydrolase activity (GO:0016787), DNA endonuclease activity, producing 3’-phosphomonoesters (GO:0016889)

GO Cellular Component (8): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), replication fork (GO:0005657), nucleolus (GO:0005730), nuclear replication fork (GO:0043596), Holliday junction resolvase complex (GO:0048476), endodeoxyribonuclease complex (GO:1905347)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
DNA Repair	2
Resolution of D-Loop Structures	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
HDR through Homologous Recombination (HRR)	1
DNA Double-Strand Break Repair	1
Homology Directed Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	4
DNA nuclease activity	2
DNA endonuclease activity, producing 3’-phosphomonoesters	2
nuclear lumen	2
cellular anatomical structure	2
reciprocal meiotic recombination	1
meiosis I cell cycle process	1
telomere organization	1
double-strand break repair via homologous recombination	1
DNA damage response	1
DNA repair	1
nucleic acid catabolic process	1
DNA-templated DNA replication maintenance of fidelity	1
mitotic S phase	1
mitotic DNA damage checkpoint signaling	1
cell population proliferation	1
mitotic recombination	1
resolution of DNA recombination intermediates	1
response to DNA damage checkpoint signaling	1
cellular response to stress	1
nucleic acid binding	1
nuclease activity	1
endonuclease activity	1
cation binding	1
flap endonuclease activity	1
catalytic activity, acting on a nucleic acid	1
binding	1
catalytic activity	1
DNA endonuclease activity	1
hydrolase activity, acting on ester bonds	1
chromosomal region	1
intracellular membrane-bounded organelle	1
chromosome	1
intracellular membraneless organelle	1
nuclear chromosome	1
nucleus	1
replication fork	1
CMG complex	1
endodeoxyribonuclease complex	1
endonuclease complex	1

Protein interactions and networks

STRING

2186 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MUS81	SLX4	Q8IY92	999
MUS81	EME1	Q96AY2	999
MUS81	SLX1A	Q9BQ83	998
MUS81	EME2	A4GXA9	996
MUS81	ERCC1	P07992	974
MUS81	ERCC4	Q92889	953
MUS81	RAD52	P43351	902
MUS81	SLX4IP	Q5VYV7	879
MUS81	FANCD2	Q9BXW9	875
MUS81	GEN1	Q17RS7	861
MUS81	RMI1	Q9H9A7	858
MUS81	BRCA2	P51587	843
MUS81	ATRX	P46100	842
MUS81	TOP3A	Q13472	842
MUS81	RAD51	Q06609	841

IntAct

61 interactions, top by confidence:

A	B	Type	Score
EME1	MUS81	psi-mi:“MI:0915”(physical association)	0.940
EME1	MUS81	psi-mi:“MI:0407”(direct interaction)	0.940
MUS81	SLX4	psi-mi:“MI:0915”(physical association)	0.880
SLX4	MUS81	psi-mi:“MI:0915”(physical association)	0.880
MUS81	SLX4	psi-mi:“MI:0403”(colocalization)	0.880
SLX4	ERCC4	psi-mi:“MI:0915”(physical association)	0.790
SLX1A	SLX4	psi-mi:“MI:0914”(association)	0.710
SLX4	ERCC1	psi-mi:“MI:0914”(association)	0.640
MUS81	ERCC4	psi-mi:“MI:0914”(association)	0.640
EME1	SLX4	psi-mi:“MI:0914”(association)	0.620
MUS81	FEN1	psi-mi:“MI:0915”(physical association)	0.600
MUS81	FEN1	psi-mi:“MI:0403”(colocalization)	0.600
SLX4	MSH2	psi-mi:“MI:0914”(association)	0.570
EME2	MUS81	psi-mi:“MI:0915”(physical association)	0.540
MUS81	ERCC1	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
FAM9B	GEMIN2	psi-mi:“MI:0914”(association)	0.530
vpr	DDB1	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
EME1		psi-mi:“MI:0572”(dna cleavage)	0.440
EME2		psi-mi:“MI:0572”(dna cleavage)	0.440

BioGRID (176): MUS81 (Affinity Capture-Western), SLX4 (Two-hybrid), MUS81 (Reconstituted Complex), MUS81 (Affinity Capture-Western), UHRF1 (Affinity Capture-Western), MUS81 (Reconstituted Complex), TERF2 (Affinity Capture-MS), EME1 (Affinity Capture-MS), CREBBP (Synthetic Growth Defect), ZNF496 (Synthetic Growth Defect), ATXN7L1 (Synthetic Growth Defect), ZNF181 (Synthetic Growth Defect), BRD9 (Synthetic Growth Defect), LTK (Synthetic Growth Defect), TMEM209 (Synthetic Growth Defect)

ESM2 similar proteins: A0A061IR73, A0A7N9VSG0, A7YSY2, D3KCC4, D3ZU57, D4A2B7, O08644, O15197, O19179, O43542, O75064, O95382, P0C0K6, P0C0K7, P51840, P52785, P52824, P54777, Q02846, Q05932, Q13470, Q13608, Q1HG60, Q3ZBE0, Q4KM32, Q5JZY3, Q643R3, Q6MG64, Q6NVG1, Q6ZPS2, Q76MJ5, Q7TNJ2, Q80SX8, Q8BYG9, Q8IZY2, Q8NFF5, Q8R5G7, Q8TDZ2, Q8WWN8, Q91V24

Diamond homologs: Q4INS6, Q4KM32, Q4WYE5, Q551H0, Q5W9E7, Q640B4, Q7SD49, Q7SXA9, Q8BJW7, Q8GT06, Q91ZJ0, Q96AY2, Q96NY9, P87231, Q04149, Q59NG5, Q5B8L2, Q754C9, A4GXA9, Q0IHN5, Q56A04, Q5NVA9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CSNK2A1	“up-regulates activity”	MUS81	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 50 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
Fanconi Anemia Pathway	6	44.0×	2e-06
Resolution of D-loop Structures through Holliday Junction Intermediates	5	39.5×	3e-05
Regulation of expression of SLITs and ROBOs	6	10.9×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair	7	29.6×	1e-06
double-strand break repair via homologous recombination	6	19.5×	6e-05
DNA repair	8	10.6×	6e-05

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	100
Likely benign	13
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2771 predictions. Top by Δscore:

Variant	Effect	Δscore
11:65860884:AGAAG:A	donor_loss	1.0000
11:65860885:GAAG:G	donor_gain	1.0000
11:65860885:GAAGG:G	donor_loss	1.0000
11:65860888:GGTG:G	donor_loss	1.0000
11:65860889:G:GC	donor_loss	1.0000
11:65860890:T:G	donor_loss	1.0000
11:65861098:GGGCG:G	donor_gain	1.0000
11:65861099:GGCG:G	donor_gain	1.0000
11:65861099:GGCGG:G	donor_gain	1.0000
11:65861100:GCG:G	donor_gain	1.0000
11:65861100:GCGG:G	donor_gain	1.0000
11:65861103:G:GG	donor_gain	1.0000
11:65861345:CGCAG:C	acceptor_loss	1.0000
11:65861346:GCAG:G	acceptor_loss	1.0000
11:65861347:CA:C	acceptor_loss	1.0000
11:65861348:A:AG	acceptor_gain	1.0000
11:65861349:G:GA	acceptor_loss	1.0000
11:65861349:G:GG	acceptor_gain	1.0000
11:65861349:GGT:G	acceptor_gain	1.0000
11:65861412:G:GT	donor_gain	1.0000
11:65861412:G:T	donor_gain	1.0000
11:65861421:G:GT	donor_gain	1.0000
11:65861432:GCCA:G	donor_gain	1.0000
11:65861436:G:GG	donor_gain	1.0000
11:65861441:G:GT	donor_gain	1.0000
11:65861442:A:T	donor_gain	1.0000
11:65861453:G:T	donor_gain	1.0000
11:65861471:G:GT	donor_gain	1.0000
11:65861479:G:GT	donor_gain	1.0000
11:65861945:A:AT	acceptor_loss	1.0000

AlphaMissense

3490 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:65863688:T:A	W310R	0.997
11:65863688:T:C	W310R	0.997
11:65863847:G:C	K335N	0.996
11:65863847:G:T	K335N	0.996
11:65863869:A:C	S343R	0.994
11:65863871:C:A	S343R	0.994
11:65863871:C:G	S343R	0.994
11:65860823:T:A	W24R	0.989
11:65860823:T:C	W24R	0.989
11:65863842:C:A	R334S	0.989
11:65863898:G:C	Q352H	0.989
11:65863898:G:T	Q352H	0.989
11:65866005:A:C	S537R	0.988
11:65866007:C:A	S537R	0.988
11:65866007:C:G	S537R	0.988
11:65864504:T:C	L356P	0.987
11:65865254:T:C	L479P	0.987
11:65863695:C:A	A312D	0.986
11:65860986:T:A	L50H	0.985
11:65863677:G:A	G306E	0.985
11:65863690:G:C	W310C	0.985
11:65863690:G:T	W310C	0.985
11:65863843:G:C	R334P	0.985
11:65863845:A:G	K335E	0.985
11:65863846:A:C	K335T	0.985
11:65861025:C:A	A63D	0.984
11:65863861:T:C	L340P	0.984
11:65861024:G:C	A63P	0.983
11:65863681:T:A	D307E	0.983
11:65863681:T:G	D307E	0.983

dbSNP variants (sampled 300 via entrez): RS1000243509 (11:65863337 G>A,T), RS1000856599 (11:65860136 T>C), RS1000963823 (11:65858287 C>G,T), RS1001230891 (11:65864163 A>G), RS1001567706 (11:65858358 G>C), RS1002000200 (11:65866577 A>C), RS1002053951 (11:65862659 A>C), RS1002305897 (11:65860640 CG>C), RS1002399478 (11:65860451 C>T), RS1002466766 (11:65865988 A>C,G), RS1002789305 (11:65861434 C>A,T), RS1003211920 (11:65867537 A>G,T), RS1004029428 (11:65857761 G>A,C,T), RS1004129928 (11:65862762 C>A,T), RS1004875474 (11:65858031 T>G)

Disease associations

OMIM: gene MIM:606591 | disease phenotypes: MIM:614437

GenCC curated gene-disease

Mondo (1): cutis laxa, autosomal recessive, type 1B (MONDO:0013754)

Orphanet (1): Autosomal recessive cutis laxa type 1 (Orphanet:90349)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001937_15	Breast cancer	9.000000e-12
GCST002481_8	Acne (severe)	3.000000e-11

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL5465380 (PROTEIN COMPLEX), CHEMBL5465381 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 87,560 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1200976	IDARUBICIN HYDROCHLORIDE	4	26,567
CHEMBL4084119	LIRAGLUTIDE	4	10,473
CHEMBL2354444	PIRARUBICIN	3	50,520

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

ChEMBL bioactivities

16 potent at pChembl≥5 of 16 total, top 16 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.25	IC50	560	nM	CHEMBL4071130
6.22	Kd	605	nM	CHEMBL4071130
6.21	IC50	610	nM	IDARUBICIN HYDROCHLORIDE
6.21	Kd	611	nM	CHEMBL4071130
6.10	IC50	790	nM	PIRARUBICIN
6.00	IC50	990	nM	CHEMBL5394285
5.93	IC50	1170	nM	LIRAGLUTIDE
5.90	IC50	1270	nM	CHEMBL5437637
5.89	IC50	1290	nM	CORILAGIN
5.84	IC50	1450	nM	GINGKOLIC ACID
5.74	IC50	1840	nM	CHEMBL1241028
5.70	IC50	1990	nM	GALLOCATECHIN GALLATE
5.54	IC50	2900	nM	CHEMBL4071130
5.48	IC50	3330	nM	CHEMBL3289398
5.38	Kd	4180	nM	DYNASORE
5.24	Kd	5780	nM	DYNASORE

PubChem BioAssay actives

16 with measured affinity, of 34 total; 12 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
3-hydroxy-N-[(E)-(2,4,5-trihydroxyphenyl)methylideneamino]naphthalene-2-carboxamide	1975164: Inhibition of human GST-tagged MUS81-ECE1 expressed in Escherichia coli BL21(DE3)Rosetta2 cells incubated for 15 mins by FRET based assay	ic50	0.5600	uM
Idarubicin Hydrochloride	1975164: Inhibition of human GST-tagged MUS81-ECE1 expressed in Escherichia coli BL21(DE3)Rosetta2 cells incubated for 15 mins by FRET based assay	ic50	0.6100	uM
(7S,9S)-7-[(2R,4S,5S,6S)-4-amino-6-methyl-5-[(2R)-oxan-2-yl]oxyoxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione	1975164: Inhibition of human GST-tagged MUS81-ECE1 expressed in Escherichia coli BL21(DE3)Rosetta2 cells incubated for 15 mins by FRET based assay	ic50	0.7900	uM
(9R)-9-[(9R)-2-carboxy-4-hydroxy-10-oxo-5-[(2R,3R,4S,5S,6S)-3,4,5,6-tetrahydroxyoxan-2-yl]oxy-9H-anthracen-9-yl]-4-hydroxy-10-oxo-5-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-9H-anthracene-2-carboxylic acid	1975164: Inhibition of human GST-tagged MUS81-ECE1 expressed in Escherichia coli BL21(DE3)Rosetta2 cells incubated for 15 mins by FRET based assay	ic50	0.9900	uM
Liraglutide	1975164: Inhibition of human GST-tagged MUS81-ECE1 expressed in Escherichia coli BL21(DE3)Rosetta2 cells incubated for 15 mins by FRET based assay	ic50	1.1700	uM
9-(2-aminoethylamino)-6-(propylamino)benzo[g]isoquinoline-5,10-dione;bis((Z)-but-2-enedioic acid)	1975164: Inhibition of human GST-tagged MUS81-ECE1 expressed in Escherichia coli BL21(DE3)Rosetta2 cells incubated for 15 mins by FRET based assay	ic50	1.2700	uM
[(1S,19R,21S,22R,23R)-6,7,8,11,12,13,22,23-octahydroxy-3,16-dioxo-2,17,20-trioxatetracyclo[17.3.1.04,9.010,15]tricosa-4,6,8,10,12,14-hexaen-21-yl] 3,4,5-trihydroxybenzoate	1975164: Inhibition of human GST-tagged MUS81-ECE1 expressed in Escherichia coli BL21(DE3)Rosetta2 cells incubated for 15 mins by FRET based assay	ic50	1.2900	uM
2-hydroxy-6-[(Z)-pentadec-8-enyl]benzoic acid	1975164: Inhibition of human GST-tagged MUS81-ECE1 expressed in Escherichia coli BL21(DE3)Rosetta2 cells incubated for 15 mins by FRET based assay	ic50	1.4500	uM
4,5,6,7-tetrachloroindene-1,3-dione	1975164: Inhibition of human GST-tagged MUS81-ECE1 expressed in Escherichia coli BL21(DE3)Rosetta2 cells incubated for 15 mins by FRET based assay	ic50	1.8400	uM
[(2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate	1975164: Inhibition of human GST-tagged MUS81-ECE1 expressed in Escherichia coli BL21(DE3)Rosetta2 cells incubated for 15 mins by FRET based assay	ic50	1.9900	uM
N-[2-(dimethylamino)ethyl]-12-oxo-12H-benzo[g]pyrido[2,1-b]quinazoline-4-carboxamide	1975164: Inhibition of human GST-tagged MUS81-ECE1 expressed in Escherichia coli BL21(DE3)Rosetta2 cells incubated for 15 mins by FRET based assay	ic50	3.3300	uM
N-[(E)-(3,4-dihydroxyphenyl)methylideneamino]-3-hydroxynaphthalene-2-carboxamide	1975177: Binding affinity to human GST-tagged MUS81-ECE2 expressed in Escherichia coli BL21(DE3)Rosetta2 cells assessed as dissociation constant by Surface plasmon resonance analysis	kd	4.1800	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	increases sumoylation, affects response to substance, decreases reaction, increases expression	2
Valproic Acid	affects expression, increases methylation	2
Cyclosporine	increases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
bisphenol A	decreases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
sodium chromate(VI)	decreases expression, decreases reaction, increases expression	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	increases expression	1
CPG-oligonucleotide	decreases expression	1
K 7174	increases expression	1
abrine	increases expression	1
olaparib	affects response to substance	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Caffeine	decreases phosphorylation	1
Camptothecin	affects response to substance	1

ChEMBL screening assays

17 unique, capped per target: 17 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5327666	Binding	Inhibition of human GST-tagged MUS81-ECE1 expressed in Escherichia coli BL21(DE3)Rosetta2 cells incubated for 15 mins by FRET based assay	Identification of small-molecule inhibitors of human MUS81-EME1/2 by FRET-based high-throughput screening. — Bioorg Med Chem

Cellosaurus cell lines

10 cell lines: 10 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_HE06	NALM-6 MUS81(-/-)	Cancer cell line	Male
CVCL_SZ37	HAP1 MUS81 (-) 1	Cancer cell line	Male
CVCL_SZ38	HAP1 MUS81 (-) 2	Cancer cell line	Male
CVCL_SZ39	HAP1 MUS81 (-) 3	Cancer cell line	Male
CVCL_SZ40	HAP1 MUS81 (-) 4	Cancer cell line	Male
CVCL_SZ41	HAP1 MUS81 (-) 5	Cancer cell line	Male
CVCL_SZ42	HAP1 MUS81 (-) 6	Cancer cell line	Male
CVCL_SZ43	HAP1 MUS81 (-) 7	Cancer cell line	Male
CVCL_SZ44	HAP1 MUS81 (-) 8	Cancer cell line	Male
CVCL_SZ45	HAP1 MUS81 (-) 9	Cancer cell line	Male

Clinical trials (associated diseases)

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