MRE11

Summary

MRE11 (MRE11 double strand break repair nuclease, HGNC:7230) is a protein-coding gene on chromosome 11q21, encoding Double-strand break repair protein MRE11 (P49959). Core component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis. In precision oncology, MRE11 Frameshift confers sensitivity to Olaparib in Prostate Cancer (CIViC Level B); 1 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 56.0% of cell lines).

This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3’ to 5’ exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3’ to 5’ exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms.

Source: NCBI Gene 4361 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ataxia-telangiectasia-like disorder 1 (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 2,458 total — 75 pathogenic, 78 likely-pathogenic
• Phenotypes (HPO): 56
• Druggable target: yes
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Cancer dependency (DepMap): dependent in 56.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_005591

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7230
Approved symbol	MRE11
Name	MRE11 double strand break repair nuclease
Location	11q21
Locus type	gene with protein product
Status	Approved
Aliases	ATLD
Ensembl gene	ENSG00000020922
Ensembl biotype	protein_coding
OMIM	600814
Entrez	4361

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 21 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000323929, ENST00000323977, ENST00000393241, ENST00000407439, ENST00000535120, ENST00000536144, ENST00000536754, ENST00000538923, ENST00000540013, ENST00000541157, ENST00000856310, ENST00000856311, ENST00000856312, ENST00000856313, ENST00000856314, ENST00000856315, ENST00000856316, ENST00000936194, ENST00000936195, ENST00000936196, ENST00000936197, ENST00000944919, ENST00000944920, ENST00000944921

RefSeq mRNA: 3 — MANE Select: NM_005591 NM_001330347, NM_005590, NM_005591

CCDS: CCDS81617, CCDS8298, CCDS8299

Canonical transcript exons

ENST00000323929 — 20 exons

Exon	Start	End
ENSE00000842836	94429911	94429986
ENSE00000842838	94435832	94435899
ENSE00000842839	94437177	94437235
ENSE00000842843	94445810	94445893
ENSE00000842844	94447219	94447438
ENSE00000842846	94456276	94456338
ENSE00001265684	94415570	94420181
ENSE00002231197	94493791	94493844
ENSE00003472465	94476289	94476403
ENSE00003495907	94479674	94479761
ENSE00003521873	94490833	94490965
ENSE00003554122	94464113	94464239
ENSE00003569515	94478735	94478876
ENSE00003594903	94471574	94471759
ENSE00003601626	94467813	94467893
ENSE00003634403	94492782	94492906
ENSE00003643226	94485924	94486084
ENSE00003644975	94459408	94459581
ENSE00003648102	94460936	94461036
ENSE00003655738	94470471	94470642

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 93.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.6577 / max 357.8567, expressed in 1762 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121846	15.1602	1747
121847	2.3400	1179
121845	0.1576	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	93.46	gold quality
oocyte	CL:0000023	92.78	gold quality
secondary oocyte	CL:0000655	92.31	gold quality
tendon	UBERON:0000043	89.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.59	gold quality
sural nerve	UBERON:0015488	88.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.55	gold quality
colonic epithelium	UBERON:0000397	87.03	gold quality
monocyte	CL:0000576	86.02	gold quality
mononuclear cell	CL:0000842	85.55	gold quality
leukocyte	CL:0000738	85.32	gold quality
rectum	UBERON:0001052	84.13	gold quality
ventricular zone	UBERON:0003053	83.73	gold quality
adrenal tissue	UBERON:0018303	83.48	gold quality
tonsil	UBERON:0002372	82.96	gold quality
tendon of biceps brachii	UBERON:0008188	82.81	silver quality
endometrium epithelium	UBERON:0004811	82.49	gold quality
hair follicle	UBERON:0002073	81.87	silver quality
islet of Langerhans	UBERON:0000006	81.65	gold quality
vermiform appendix	UBERON:0001154	81.11	gold quality
endometrium	UBERON:0001295	81.05	gold quality
bone marrow cell	CL:0002092	80.90	gold quality
body of pancreas	UBERON:0001150	80.89	gold quality
granulocyte	CL:0000094	80.84	gold quality
ganglionic eminence	UBERON:0004023	80.69	gold quality
stromal cell of endometrium	CL:0002255	80.53	gold quality
skin of abdomen	UBERON:0001416	80.52	gold quality
smooth muscle tissue	UBERON:0001135	80.50	gold quality
pancreas	UBERON:0001264	80.46	gold quality
lymph node	UBERON:0000029	80.38	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): LEF1, MYCN

miRNA regulators (miRDB)

126 targeting MRE11, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-495-3P	99.96	72.81	4197
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-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 56.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Major target for inactivation in mismatch repair-defective cells and may contribute to the development of colorectal cancer. (PMID:11850399)
• Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex (PMID:12124628)
• activation in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes (PMID:12660252)
• Mre11 complex is required for both ATM activation and the ATM-dependent G(2)/M checkpoint in response to double stranded breaks. (PMID:14657032)
• WRN associates with the Mre11 complex via binding to Nbs1 in vitro and in vivo. (PMID:15026416)
• Functional and structural characterization of a nuclease-deficient Mre11 protein termed mre11-3. (PMID:15047855)
• MRE11 is a new common target in the mismatch repair deficient tumorigenesis and has a role in colorectal carcinogenesis (PMID:15048091)
• Replication protein A, Mre11, Rad50 and Nbs1 bind and have roles in DNA repair (PMID:15180989)
• Two hours at 41 degrees C did not increase the radiation sensitivity of cells with a reduced Mre11 protein level following a 24-h siRNA treatment. (PMID:15195510)
• Nibrin, Mre11 and Rad50 also act as adaptors for some downstream Atm phosphorylation events (PMID:15234984)
• MRE11 gene mutations affected ATM-dependent responses in radiosensitive ataxia-telangiectasia-like disorder family. (PMID:15269180)
• MRE11 expression is impaired in gastric cancer with microsatellite instability (PMID:15319296)
• Data show that Mre11 complex proteins are present in neurons of the adult human cortex and cerebellum, and suggest that loss of the complex may be associated with the pathogenesis of Alzheimer disease. (PMID:15337312)
• early-onset, slowly progressive, ataxia plus ocular apraxia phenotype = ataxia telangiectasia-like disorder (ATLD) (PMID:15574463)
• the Mre11/Rad50/Nbs1 (MRN) complex may play a more universal role in the recognition and response to DNA lesions of all types, whereas the role of RPA may be limited to certain subsets of lesions (PMID:15653682)
• findings show that the Mre11-Rad50-Nbs1 (MRN) complex acts as a double-strand break sensor for ATM and recruits ATM to broken DNA molecules (PMID:15790808)
• hMRE11 represents a functional component of the DNA mismatch repair pathway (PMID:15864295)
• The MRE11-RAD50-NBS1 complex accelerates somatic hypermutation and gene conversion of immunoglobulin variable regions. (PMID:15937485)
• These results suggest that MRE11 methylation regulates its association with nuclear structures such as PML nuclear bodies and sites of DNA damage. (PMID:15970667)
• the dynamic architecture of human Rad50/Mre11/Nbs1 is markedly affected by DNA binding (PMID:16163361)
• Adenovirus 5 exploits the cellular aggresome response to accelerate inactivation of MRE11-RAD50-NBS1 (MRN) complexes that otherwise inhibit viral DNA replication and packaging. (PMID:16254336)
• We show that Mre11 are required for the processing of DNA double-strand breaks (DSBs) to generate the replication protein A (RPA)-coated ssDNA that is needed for ATR recruitment and the subsequent phosphorylation and activation of Chk1. (PMID:16327781)
• the data are not compatible with selective pressures during tumorigenesis promoting the functional loss of BRCA2 and MRE11 in microsatellite unstable tumors, but fit closely with an absence of selective pressures acting on BRCA2 and MRE11 gene status (PMID:16417627)
• ATM and Mre11 may stimulate the ATR signaling pathway by converting DNA damage generated by ionizing radiation into structures that recruit and activate ATR (PMID:16431910)
• the Mre11-Rad50-Nbs1 complex stayed in the nucleus and remained intact in response to hypertonicity (PMID:16788144)
• Mre11 stabilizes Nbs1 and Rad50 and MRN activates Chk2 downstream from ATM in response to replication-mediated DNA double strand breaks (PMID:16905549)
• Part played by Mre11 in telomere maintenance may not be important for the progression of lung adenoma-carcinoma although some role for it in carcinogenesis cannot be completely ruled out. (PMID:16948520)
• MRE11, but not RAD50 or NBS1 variants, may play a role in non-Hodgkin’s lymphoma (PMID:17169801)
• maintenance of higher expression of Ku70 and Mre11 may be responsible for keeping longer life span observed in the longevity group (PMID:17202845)
• Mre11/Rad50 complexes from three organisms catalyze the reversible adenylate kinase reaction in vitro. (PMID:17349953)
• The results are consistent with a model in which Mre11 interferes with DNA replication when it is localized at viral DNA replication foci. (PMID:17477953)
• the Mre11-Rad50-Nbs1 complex plays critical roles both upstream and downstream of ATR to regulate the S-phase checkpoint when replication forks are stalled (PMID:17526493)
• microsatelite instability and alterations in the MRE11 and RAD50 repeats that are associated with the reduced protein expression and functional impairment of the MRE11-RAD50-NBS1 complex in Lynch syndrome (PMID:17534377)
• Data demonstrate that Mre11/Rad50/Nbs1 interacts with replication protein A in unperturbed cells, that the interaction is regulated by cyclin-dependent kinases, and that this interaction is needed for MRN to correctly localize to replication centers. (PMID:17591703)
• the MRN (MRE11/RAD50/NBS1)complex, and especially NBS1, is required for alternative lengthening of telomeres (PMID:17693401)
• TRF1 association with telomeres induced by ATM inhibition is abrogated in cells lacking MRE11 or NBS1, suggesting that MRN and ATM function in the same pathway controlling TRF1 binding to telomeres (PMID:17694070)
• These data support a role for RPA as an initial signal/sensor for DNA damage that facilitates recruitment of MRE11/RAD50/NBS1 and ATM/ATR to sites of damage, where they then work together to fully activate the DNA damage response. (PMID:17700070)
• Studies suggest new roles of Mre11/Rad50/Nbs1 complex in the maintenance of genome stability through preventing rereplication and rereplication-associated double-stranded breaks when licensing control is compromised. (PMID:17715134)
• Mre11/Rad50/Nbs1 complex (MRN) poses a barrier to adeno-associated virus and that the helper function provided by E1b55K/E4orf6 involves MRN degradation. (PMID:17898048)
• Hypothesis examined in a study of 559 breast cancer patients of single-nucleotide polymorphisms in Mre11, Rad50, and Nbs1 and by the in vivo detection of binding between Mre11 and BRCA1, encoded by the breast cancer susceptibility gene BRCA1. (PMID:17932350)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mre11a	ENSDARG00000105014
mus_musculus	Mre11a	ENSMUSG00000031928
rattus_norvegicus	Mre11	ENSRNOG00000009506
drosophila_melanogaster	mre11	FBGN0020270
caenorhabditis_elegans		WBGENE00003405

Protein

Protein identifiers

Double-strand break repair protein MRE11 — P49959 (reviewed: P49959)

Alternative names: Meiotic recombination 11 homolog 1, Meiotic recombination 11 homolog A

All UniProt accessions (5): P49959, F5GXT0, F5H256, F5H742, F8W7U8

UniProt curated annotations — full annotation on UniProt →

Function. Core component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis. The MRN complex is involved in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR), an error-free mechanism which primarily occurs during S and G2 phases. The complex (1) mediates the end resection of damaged DNA, which generates proper single-stranded DNA, a key initial steps in HR, and is (2) required for the recruitment of other repair factors and efficient activation of ATM and ATR upon DNA damage. Within the MRN complex, MRE11 possesses both single-strand endonuclease activity and double-strand-specific 3’-5’ exonuclease activity. After DSBs, MRE11 is loaded onto DSBs sites and cleaves DNA by cooperating with RBBP8/CtIP to initiate end resection. MRE11 first endonucleolytically cleaves the 5’ strand at DNA DSB ends to prevent non-homologous end joining (NHEJ) and licence HR. It then generates a single-stranded DNA gap via 3’ to 5’ exonucleolytic degradation to create entry sites for EXO1- and DNA2-mediated 5’ to 3’ long-range resection, which is required for single-strand invasion and recombination. RBBP8/CtIP specifically promotes the endonuclease activity of MRE11 to clear protein-DNA adducts and generate clean double-strand break ends. MRE11 endonuclease activity is also enhanced by AGER/RAGE. The MRN complex is also required for DNA damage signaling via activation of the ATM and ATR kinases: the nuclease activity of MRE11 is not required to activate ATM and ATR. The MRN complex is also required for the processing of R-loops. The MRN complex is involved in the activation of the cGAS-STING pathway induced by DNA damage during tumorigenesis: the MRN complex acts by displacing CGAS from nucleosome sequestration, thereby activating it. In telomeres the MRN complex may modulate t-loop formation. MRE11 contains two DNA-binding domains (DBDs), enabling it to bind both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA).

Subunit / interactions. Component of the MRN complex composed of two heterodimers RAD50 and MRE11 associated with a single NBN. The MRN complexes dimerize on DNA to form joined MRN-MRN oligomers required for DNA double-strand break repair. As part of the MRN complex, interacts with MCM9; the interaction recruits the complex to DNA repair sites. Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN. Found in a complex with TERF2. Interacts with DCLRE1C/Artemis and DCLRE1B/Apollo. Interacts with ATF2. Interacts with EXD2. Interacts with MRNIP. Interacts with SAMHD1; leading to stimulate 3’-5’ exonuclease activity. Interacts (when ubiquitinated) with UBQLN4 (via its UBA domain). Interacts with CYREN (via XLF motif). Interacts with GFI1; promoting methylation by PRMT1. Interacts with DYNLL1; inhibiting the activity of MRE11. Interacts with C1QBP and RAD50; interaction takes place in absence of DNA damage to form the MRC (MRE11-RAD50-C1QBP) complex that inhibits the activity of MRE11. Interacts with AGER/RAGE. AGER is recruited to DNA double-strand break sites where it enhances MRE11 endonuclease activity to promote DNA repair. (Microbial infection) Interacts with herpes simplex virus 1 protein UL12.

Subcellular location. Nucleus. Chromosome. Telomere.

Post-translational modifications. Phosphorylated by ATM at Ser-676 and Ser-678 in response to DNA damage, promoting MRE11 activity: phosphorylation activates MRE11 by preventing the interaction between MRE11 and the C1QBP inhibitor. Phosphorylation at Ser-649 by PLK1 primes for phosphorylation at Ser-688 by CK2, inhibiting recruitment of the MRN complex to DNA damage sites. Asymmetric dimethylation by PRMT1 promotes MRE11 exonuclease activity. Lactylation at Lys-673 by CREBBP/CBP in response to DNA damage promotes DNA binding and MRE11 activity. Acetylated on lysine residues by KAT2A /GCN5. Ubiquitinated following DNA damage. Ubiquitination triggers interaction with UBQLN4, leading to MRE11 removal from chromatin and degradation by the proteasome. Ubiquitinated at Lys-339 and Lys-480 by RNF126 via ‘Lys-27’- and ‘Lys-29’-linked polyubiquitin chains, promoting the exonuclease activity of MRE11. SUMOylated by PIAS1, stabilizing MRE11 on chromatin during end resection. DeSUMOylated by SENP3 following removal from DNA double-strand breaks (DSBs). Ufmylation at Lys-282 promotes MRE11 activity and is required for activation of the ATM and ATR kinases by the MRN complex. (Microbial infection) Following infection by adenovirus E4, ubiquitinated and degraded by a SCF-like E3 ubiquitin ligase complex containing viral proteins E1B-55K and E4-ORF6.

Disease relevance. Ataxia-telangiectasia-like disorder 1 (ATLD1) [MIM:604391] A rare disorder characterized by progressive cerebellar ataxia, dysarthria, abnormal eye movements, and absence of telangiectasia. ATLD patients show normal levels of total IgG, IgA and IgM, although there may be reduced levels of specific functional antibodies. At the cellular level, ATLD exhibits hypersensitivity to ionizing radiation and radioresistant DNA synthesis. The disease is caused by variants affecting the gene represented in this entry. Defects in MRE11 can be a cause of nephronophthisis-related ciliopathies (NPHP-RC), a group of recessive diseases that affect kidney, retina and brain. A homozygous truncating mutation MRE11 has been found in patients with cerebellar vermis hypoplasia, ataxia and dysarthria.

Activity regulation. Interaction with SAMHD1 stimulates the double-strand-specific 3’-5’ exonuclease activity. RBBP8/CtIP specifically promotes the endonuclease activity to clear protein-DNA adducts and generate clean double-strand break ends. DYNLL1-binding inhibits the activity of MRE11. MRE11 activity is inhibited by C1QBP: in absence of DNA damage, C1QBP interacts with unphosphorylated MRE11, preventing formation and activity of the MRN complex. The mirin-derivative PFM39, specifically inhibits the 3’-5’ exonuclease activity. The N-alkylated mirin-derivatives PFM03 and PFM01 specifically inhibit the endonuclease activity.

Similarity. Belongs to the MRE11/RAD32 family.

Isoforms (3)

UniProt ID	Names	Canonical?
P49959-1	1	yes
P49959-2	2
P49959-3	3

RefSeq proteins (3): NP_001317276, NP_005581, NP_005582* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003701	Mre11	Family
IPR004843	Calcineurin-like_PHP	Domain
IPR007281	Mre11_DNA-bd	Domain
IPR029052	Metallo-depent_PP-like	Homologous_superfamily
IPR038487	Mre11_capping_dom	Homologous_superfamily
IPR041796	Mre11_N	Domain

Pfam: PF00149, PF04152

UniProt features (135 total): mutagenesis site 23, strand 22, modified residue 21, sequence variant 16, helix 12, turn 9, binding site 8, cross-link 8, compositionally biased region 5, region of interest 4, splice variant 2, initiator methionine 1, chain 1, active site 1, short sequence motif 1, sequence conflict 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
8K00	X-RAY DIFFRACTION	1.4
7ZQY	X-RAY DIFFRACTION	2.51
9Q9K	ELECTRON MICROSCOPY	2.59
9Q9J	ELECTRON MICROSCOPY	2.71
9Q9I	ELECTRON MICROSCOPY	2.79
9Q9M	ELECTRON MICROSCOPY	2.81
3T1I	X-RAY DIFFRACTION	3
9Q9H	ELECTRON MICROSCOPY	3.11
9ULO	ELECTRON MICROSCOPY	3.91
8BAH	ELECTRON MICROSCOPY	4.13

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49959-F1	76.05	0.48

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 (1): 129 (proton donor)

Ligand- & substrate-binding residues (8): 20; 22; 60; 60; 128; 217; 245; 247

Post-translational modifications (29): 2, 2, 275, 570, 572, 574, 576, 577, 580, 587, 592, 594, 619, 641, 649, 673, 676, 678, 688, 689 …

Mutagenesis-validated functional residues (23):

Position	Phenotype
80	abolished interaction with nbn.
87–117	abolished interaction with nbn.
88	does not affect interaction with nbn.
117	abolished interaction with nbn.
121	abolished interaction with nbn.
129–130	lacks the exonuclease activity.
255	in 4kr mutant; strongly decreased sumoylation; when associated with r-384, r-416 and r-467.
282	abolished ufmylation.
339	abolished ubiquitination by rnf126; when associated with r-480.
384	in 4kr mutant; strongly decreased sumoylation; when associated with r-255, r-416 and r-467.
416	in 4kr mutant; strongly decreased sumoylation; when associated with r-255, r-384 and r-467.
467	in 4kr mutant; strongly decreased sumoylation; when associated with r-255, r-384 and r-416.
480	abolished ubiquitination by rnf126; when associated with r-339.
531	does not affect phosphorylation by atm; when associated with a-590.
570–594	abolished methylation, leading to decreased exonuclease activity.
572–576	abolished interaction with c1qbp.
590	does not affect phosphorylation by atm; when associated with a-531.
649	decreased phosphorylation; when associated with a-688.
649	mimics phosphorylation; decreased ability to mediate dna repair; when associated with d-688.
673	abolished lactylation by crebbp/cbp, leading to decreased dna-binding.
676–678	impaired phosphorylation by atm, preventing interaction with c1qbp.
688	decreased phosphorylation; when associated with a-649.
688	mimics phosphorylation; decreased ability to mediate dna repair; when associated with d-649.

Function

Pathways and Gene Ontology

Reactome pathways

49 pathways

ID	Pathway
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-3270619	IRF3-mediated induction of type I IFN
R-HSA-5685938	HDR through Single Strand Annealing (SSA)
R-HSA-5685939	HDR through MMEJ (alt-NHEJ)
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5693548	Sensing of DNA Double Strand Breaks
R-HSA-5693554	Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693568	Resolution of D-loop Structures through Holliday Junction Intermediates
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693579	Homologous DNA Pairing and Strand Exchange
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-5693616	Presynaptic phase of homologous DNA pairing and strand exchange
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-912446	Meiotic recombination
R-HSA-9701192	Defective homologous recombination repair (HRR) due to BRCA1 loss of function
R-HSA-9704331	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function
R-HSA-9704646	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function
R-HSA-9709570	Impaired BRCA2 binding to RAD51
R-HSA-9709603	Impaired BRCA2 binding to PALB2
R-HSA-1474165	Reproduction
R-HSA-1500620	Meiosis
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-1834941	STING mediated induction of host immune responses
R-HSA-212436	Generic Transcription Pathway

MSigDB gene sets: 448 (showing top): PID_FANCONI_PATHWAY, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOMF_ENDONUCLEASE_ACTIVITY, REACTOME_INNATE_IMMUNE_SYSTEM, PID_TELOMERASE_PATHWAY, GOBP_TELOMERE_CAPPING, BIOCARTA_ATM_PATHWAY, GOMF_NUCLEASE_ACTIVITY

GO Biological Process (29): regulation of mitotic recombination (GO:0000019), telomere maintenance (GO:0000723), double-strand break repair via homologous recombination (GO:0000724), DNA double-strand break processing (GO:0000729), DNA repair (GO:0006281), double-strand break repair (GO:0006302), double-strand break repair via nonhomologous end joining (GO:0006303), DNA recombination (GO:0006310), DNA damage response (GO:0006974), telomere maintenance via telomerase (GO:0007004), sister chromatid cohesion (GO:0007062), mitotic G2 DNA damage checkpoint signaling (GO:0007095), homologous chromosome pairing at meiosis (GO:0007129), reciprocal meiotic recombination (GO:0007131), cell population proliferation (GO:0008283), mitotic intra-S DNA damage checkpoint signaling (GO:0031573), telomeric 3’ overhang formation (GO:0031860), positive regulation of telomere maintenance (GO:0032206), homologous recombination (GO:0035825), meiotic DNA double-strand break formation (GO:0042138), negative regulation of apoptotic process (GO:0043066), mitotic G2/M transition checkpoint (GO:0044818), R-loop processing (GO:0062176), mitochondrial double-strand break repair via homologous recombination (GO:0097552), DNA strand resection involved in replication fork processing (GO:0110025), positive regulation of double-strand break repair (GO:2000781), negative regulation of double-strand break repair via nonhomologous end joining (GO:2001033), chromosome organization (GO:0051276), meiotic cell cycle (GO:0051321)

GO Molecular Function (15): single-stranded DNA endonuclease activity (GO:0000014), double-stranded DNA binding (GO:0003690), nuclease activity (GO:0004518), DNA endonuclease activity (GO:0004520), 3’-5’-DNA exonuclease activity (GO:0008296), 3’-5’ exonuclease activity (GO:0008408), manganese ion binding (GO:0030145), identical protein binding (GO:0042802), cadherin binding (GO:0045296), DNA binding (GO:0003677), DNA helicase activity (GO:0003678), endonuclease activity (GO:0004519), exonuclease activity (GO:0004527), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (12): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), replication fork (GO:0005657), cytoplasm (GO:0005737), cytosol (GO:0005829), PML body (GO:0016605), Mre11 complex (GO:0030870), site of double-strand break (GO:0035861), BRCA1-C complex (GO:0070533), chromosomal region (GO:0098687), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	3
DNA Double Strand Break Response	2
Resolution of D-Loop Structures	2
Defective homologous recombination repair (HRR) due to PALB2 loss of function	2
Innate Immune System	1
Cellular Senescence	1
STING mediated induction of host immune responses	1
Homology Directed Repair	1
DNA Double-Strand Break Repair	1
HDR through Homologous Recombination (HRR)	1
Homologous DNA Pairing and Strand Exchange	1
Regulation of TP53 Activity	1
G2/M Checkpoints	1
Meiosis	1
Diseases of DNA Double-Strand Break Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	5
cellular anatomical structure	5
double-strand break repair	3
mitotic DNA damage checkpoint signaling	2
hydrolase activity, acting on ester bonds	2
nuclease activity	2
chromosome	2
nuclear protein-containing complex	2
regulation of DNA recombination	1
mitotic recombination	1
telomere organization	1
recombinational repair	1
5’-3’ DNA exonuclease activity	1
DNA damage response	1
DNA repair	1
cellular response to stress	1
telomerase activity	1
RNA-templated DNA biosynthetic process	1
telomere maintenance via telomere lengthening	1
telomere-telomerase complex assembly	1
cell cycle process	1
chromosome organization	1
mitotic G2 phase	1
mitotic G2/M transition checkpoint	1
homologous chromosome segregation	1
chromosome organization involved in meiotic cell cycle	1
meiosis I	1
reciprocal homologous recombination	1
meiotic cell cycle process	1
cellular process	1
mitotic S phase	1
telomere capping	1
DNA strand elongation	1
telomere maintenance	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
DNA recombination	1
meiosis I cell cycle process	1
DNA endonuclease activity	1

Protein interactions and networks

STRING

3170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MRE11	NBN	O60934	997
MRE11	RAD50	Q92878	997
MRE11	BRCA1	P38398	974
MRE11	ATM	Q13315	941
MRE11	BRCA2	P51587	932
MRE11	RAD51	Q06609	914
MRE11	RBBP8	Q99708	857
MRE11	PMS2	P54278	827
MRE11	XRCC2	O43543	811
MRE11	RAD51D	O75771	808
MRE11	K7EN88	K7EN88	807
MRE11	RAD51C	O43502	807
MRE11	CHEK2	O96017	790
MRE11	SMC1A	Q14683	775
MRE11	WRN	Q14191	763

IntAct

172 interactions, top by confidence:

A	B	Type	Score
MDC1	NBN	psi-mi:“MI:0914”(association)	0.970
H2AX	NBN	psi-mi:“MI:0914”(association)	0.860
MRE11	NBN	psi-mi:“MI:0914”(association)	0.820
MRE11	NBN	psi-mi:“MI:0407”(direct interaction)	0.820
MRE11	NBN	psi-mi:“MI:0915”(physical association)	0.820
NBN	MRE11	psi-mi:“MI:0914”(association)	0.820
H2AX	MRE11	psi-mi:“MI:0914”(association)	0.810
MRE11	H2AX	psi-mi:“MI:0403”(colocalization)	0.810
MRE11	H2AX	psi-mi:“MI:0915”(physical association)	0.810
MRE11	RAD50	psi-mi:“MI:0403”(colocalization)	0.780
RAD50	NBN	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RBBP8	MRE11	psi-mi:“MI:0914”(association)	0.670
MDC1	MRE11	psi-mi:“MI:0914”(association)	0.670
RBBP8	MRE11	psi-mi:“MI:0915”(physical association)	0.670
FANCD2	MRE11	psi-mi:“MI:0915”(physical association)	0.650

BioGRID (590): MRE11A (Affinity Capture-MS), MRE11A (Reconstituted Complex), MRE11A (Affinity Capture-MS), MRE11A (Affinity Capture-MS), MRE11A (Affinity Capture-MS), MRE11A (Affinity Capture-MS), MRE11A (Reconstituted Complex), MRE11A (Affinity Capture-MS), MRE11A (Affinity Capture-MS), MRE11A (Affinity Capture-MS), MRE11A (Affinity Capture-Western), MRE11A (Affinity Capture-MS), AIDA (Co-fractionation), CHAMP1 (Co-fractionation), DRC1 (Co-fractionation)

ESM2 similar proteins: A1Z9L3, A4R0E6, A8N936, B0E412, D1Z6B1, F4IJV4, G0RYR3, O42643, O45244, O60182, P32829, P35600, P38630, P49959, Q09530, Q09683, Q0U5F2, Q1DU75, Q23255, Q29FE1, Q2H0I3, Q2H9L1, Q2HGJ1, Q2MHH3, Q2MHH4, Q38953, Q4IJP1, Q4WVH4, Q5AVC7, Q5BH89, Q60HE6, Q61216, Q6CHI1, Q6FRZ5, Q759T6, Q7F1M0, Q7SA95, Q7SB74, Q7SD49, Q7Z7W5

Diamond homologs: G0RYR3, P32829, P49959, Q09683, Q23255, Q25AA3, Q60HE6, Q61216, Q7XQR9, Q8SRV0, Q9C291, Q9IAM7, Q9JIM0, Q9UVN9, Q9W6K1, Q9XGM2, D4GUK0, Q8U1N9, Q9HRW4, Q9UZC9, O58686

SIGNOR signaling

18 interactions.

A	Effect	B	Mechanism
MRE11	up-regulates	NBN	binding
RAD50	up-regulates	MRE11	binding
MRE11	up-regulates	ATM	binding
RPA2	up-regulates	MRE11	binding
UBQLN4	“up-regulates activity”	MRE11	binding
MRE11	“up-regulates activity”	PIH1D1	binding
PLK1	“down-regulates activity”	MRE11	phosphorylation
PARP1	“up-regulates activity”	MRE11	relocalization
WDCP	“up-regulates activity”	MRE11	binding
RPS6KA2	“down-regulates activity”	MRE11	phosphorylation
ATM	up-regulates	MRE11	phosphorylation
MRE11	“form complex”	MRE11/RAD50/NBS1	binding
CSNK2A1	“up-regulates activity”	MRE11	phosphorylation
RPS6KB1	“down-regulates quantity by destabilization”	MRE11	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 149 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
Impaired BRCA2 binding to PALB2	5	21.8×	2e-04
Impaired BRCA2 binding to RAD51	7	20.6×	7e-06
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	5	20.1×	2e-04
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	5	20.1×	2e-04
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	5	20.1×	2e-04
HDR through Single Strand Annealing (SSA)	7	19.5×	8e-06
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	5	18.8×	3e-04
Presynaptic phase of homologous DNA pairing and strand exchange	7	18.1×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein localization to site of double-strand break	5	39.9×	2e-05
positive regulation of telomere maintenance	5	19.3×	5e-04
DNA damage checkpoint signaling	6	17.8×	1e-04
positive regulation of DNA repair	6	16.3×	2e-04
telomere maintenance	8	16.2×	8e-06
positive regulation of miRNA transcription	7	15.4×	5e-05
double-strand break repair	9	13.8×	5e-06
DNA recombination	5	12.8×	3e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

2458 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	75
Likely pathogenic	78
Uncertain significance	1324
Likely benign	682
Benign	71

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1076039	NC_000011.9:g.(?94180375)(94180614_?)del	Pathogenic
1076040	NC_000011.9:g.(?94168988)(94170411_?)del	Pathogenic
1323291	NM_005591.4(MRE11):c.1018del (p.Ile340fs)	Pathogenic
1323293	NM_005591.4(MRE11):c.1552dup (p.Glu518fs)	Pathogenic
140953	NM_005591.4(MRE11):c.1090C>T (p.Arg364Ter)	Pathogenic
141813	NM_005591.4(MRE11):c.508C>T (p.Gln170Ter)	Pathogenic
1681442	NC_000011.9:g.(?94153291)(94225967_?)del	Pathogenic
1681551	NM_005591.4(MRE11):c.1979C>A (p.Ser660Ter)	Pathogenic
1681628	NM_005591.4(MRE11):c.422dup (p.Leu141fs)	Pathogenic
1799696	NM_005591.4(MRE11):c.842del (p.Lys281fs)	Pathogenic
1799704	NM_005591.4(MRE11):c.1124del (p.Pro375fs)	Pathogenic
1799732	NM_005591.4(MRE11):c.628del (p.Trp210fs)	Pathogenic
1799895	NM_005591.4(MRE11):c.1532del (p.Asn511fs)	Pathogenic
1799962	NM_005591.4(MRE11):c.988C>T (p.Gln330Ter)	Pathogenic
1800256	NM_005591.4(MRE11):c.1957G>T (p.Glu653Ter)	Pathogenic
1800257	NM_005591.4(MRE11):c.157del (p.Asp53fs)	Pathogenic
1800260	NM_005591.4(MRE11):c.1997G>A (p.Trp666Ter)	Pathogenic
1800285	NM_005591.4(MRE11):c.916C>T (p.Gln306Ter)	Pathogenic
1800352	NM_005591.4(MRE11):c.1378G>T (p.Glu460Ter)	Pathogenic
1800380	NM_005591.4(MRE11):c.1552G>T (p.Glu518Ter)	Pathogenic
1800410	NM_005591.4(MRE11):c.1196del (p.Phe399fs)	Pathogenic
182554	NM_005591.4(MRE11):c.627_628del (p.Trp210fs)	Pathogenic
186907	NM_005591.4(MRE11):c.1445_1446delinsTTAA (p.Gln482fs)	Pathogenic
187370	NM_005591.4(MRE11):c.1336del (p.Leu446fs)	Pathogenic
187699	NM_005591.4(MRE11):c.739dup (p.His247fs)	Pathogenic
2002130	NM_005591.4(MRE11):c.-4_13A[5]TGAGTACTGCAGGCCGGTCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAAATGAGTACTGCAG[1] (p.Asp5delinsGlyArgSerArgTrpLeuThrProValIleProAlaLeuTrpGluAlaGluAlaGlyGlySerArgXaaXaaXaaXaaLysLysLysLysLysLysLysLysTer)	Pathogenic
2011918	NM_005591.4(MRE11):c.1477del (p.Leu493fs)	Pathogenic
2038927	NM_005591.4(MRE11):c.1005_1006del (p.Phe335fs)	Pathogenic
2041094	NM_005591.4(MRE11):c.1920T>A (p.Tyr640Ter)	Pathogenic
233221	NM_005591.4(MRE11):c.1826dup (p.Thr610fs)	Pathogenic

SpliceAI

3861 predictions. Top by Δscore:

Variant	Effect	Δscore
11:94420043:AAAAT:A	donor_gain	1.0000
11:94420066:AG:A	donor_gain	1.0000
11:94420067:G:C	donor_gain	1.0000
11:94420087:T:TA	donor_gain	1.0000
11:94429898:A:AC	donor_gain	1.0000
11:94435827:CCTA:C	donor_loss	1.0000
11:94435828:CTAC:C	donor_loss	1.0000
11:94435829:TAC:T	donor_loss	1.0000
11:94435830:A:AC	donor_gain	1.0000
11:94435830:ACCT:A	donor_loss	1.0000
11:94435831:C:CC	donor_gain	1.0000
11:94435831:C:CG	donor_loss	1.0000
11:94435896:TCAC:T	acceptor_gain	1.0000
11:94435897:CAC:C	acceptor_gain	1.0000
11:94435897:CACC:C	acceptor_gain	1.0000
11:94435900:C:CC	acceptor_gain	1.0000
11:94435900:CTGGC:C	acceptor_loss	1.0000
11:94435904:C:CT	acceptor_gain	1.0000
11:94435905:A:T	acceptor_gain	1.0000
11:94435912:C:CT	acceptor_gain	1.0000
11:94437171:TCTTA:T	donor_loss	1.0000
11:94437172:CTTA:C	donor_loss	1.0000
11:94437173:TTA:T	donor_loss	1.0000
11:94437175:ACCTC:A	donor_loss	1.0000
11:94437176:C:A	donor_loss	1.0000
11:94437176:CCT:C	donor_gain	1.0000
11:94437231:AAAGG:A	acceptor_gain	1.0000
11:94437232:AAGG:A	acceptor_gain	1.0000
11:94437233:AGG:A	acceptor_gain	1.0000
11:94437234:GG:G	acceptor_gain	1.0000

AlphaMissense

4731 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:94459539:C:G	A457P	1.000
11:94479690:T:G	H129P	1.000
11:94459454:A:G	L485P	0.999
11:94459502:G:T	A469D	0.999
11:94459503:C:G	A469P	0.999
11:94459535:A:T	V458E	0.999
11:94459538:G:T	A457E	0.999
11:94459562:A:G	L449P	0.999
11:94459562:A:T	L449Q	0.999
11:94459565:A:G	L448P	0.999
11:94459571:A:G	L446P	0.999
11:94460967:A:G	L432P	0.999
11:94471615:G:C	S268R	0.999
11:94471615:G:T	S268R	0.999
11:94471617:T:G	S268R	0.999
11:94471619:C:T	G267E	0.999
11:94471692:A:G	W243R	0.999
11:94471692:A:T	W243R	0.999
11:94471700:A:G	L240P	0.999
11:94476299:G:C	H217D	0.999
11:94476382:A:G	L189P	0.999
11:94479688:C:G	D130H	0.999
11:94479689:A:C	H129Q	0.999
11:94479689:A:T	H129Q	0.999
11:94479691:G:C	H129D	0.999
11:94479692:A:C	N128K	0.999
11:94479692:A:T	N128K	0.999
11:94479696:C:A	G127V	0.999
11:94479696:C:T	G127D	0.999
11:94479697:C:G	G127R	0.999

dbSNP variants (sampled 300 via entrez): RS1000010414 (11:94446515 G>A), RS1000021417 (11:94446896 G>C), RS1000055780 (11:94495642 G>A), RS1000070707 (11:94488798 A>G), RS1000214641 (11:94482651 C>T), RS1000227197 (11:94474255 G>A), RS1000244384 (11:94440326 A>G), RS1000309365 (11:94482430 A>G), RS1000363874 (11:94476753 C>T), RS1000371053 (11:94502007 A>G), RS1000429279 (11:94432617 C>T), RS1000442964 (11:94488425 C>T), RS1000447663 (11:94433770 T>C,G), RS1000471854 (11:94476912 G>T), RS1000481557 (11:94432823 A>G)

Disease associations

OMIM: gene MIM:600814 | disease phenotypes: MIM:604391, MIM:167000, MIM:109800

GenCC curated gene-disease

Disease	Classification	Inheritance
ataxia-telangiectasia-like disorder 1	Definitive	Autosomal recessive
breast cancer	Disputed Evidence	Autosomal dominant
prostate cancer	Disputed Evidence	Autosomal dominant
familial ovarian cancer	Refuted Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hereditary breast carcinoma	Refuted	AD
familial ovarian cancer	Refuted	AD

Mondo (18): ataxia-telangiectasia-like disorder (MONDO:0011457), hereditary neoplastic syndrome (MONDO:0015356), ataxia-telangiectasia-like disorder 1 (MONDO:0024557), hereditary breast ovarian cancer syndrome (MONDO:0003582), breast carcinoma (MONDO:0004989), ovarian cancer (MONDO:0008170), dementia (MONDO:0001627), depressive disorder (MONDO:0002050), dystonic disorder (MONDO:0003441), parkinsonian disorder (MONDO:0021095), ovarian neoplasm (MONDO:0021068), premature menopause (MONDO:0001119), colonic neoplasm (MONDO:0005401), eccrine porocarcinoma (MONDO:0006189), urinary bladder cancer (MONDO:0001187)

Orphanet (5): Inherited cancer-predisposing syndrome (Orphanet:140162), Ataxia-telangiectasia-like disorder (Orphanet:251347), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Rare ovarian cancer (Orphanet:213500), NON RARE IN EUROPE: Bladder cancer (Orphanet:157980)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000298	Mask-like facies
HP:0000514	Slow saccadic eye movements
HP:0000571	Hypometric saccades
HP:0000617	Abnormality of ocular smooth pursuit
HP:0000640	Gaze-evoked nystagmus
HP:0000641	Dysmetric saccades
HP:0000657	Oculomotor apraxia
HP:0000750	Delayed speech and language development
HP:0000815	Hypergonadotropic hypogonadism
HP:0001009	Telangiectasia
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001266	Choreoathetosis
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001310	Dysmetria
HP:0001315	Reduced tendon reflexes
HP:0001320	Cerebellar vermis hypoplasia
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001382	Joint hypermobility
HP:0001761	Pes cavus
HP:0002061	Lower limb spasticity
HP:0002066	Gait ataxia
HP:0002072	Chorea
HP:0002075	Dysdiadochokinesis
HP:0002080	Intention tremor

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003674_2	Obstructive sleep apnea trait (apnea hypopnea index)	2.000000e-08
GCST009391_1865	Metabolite levels	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007817	sleep apnea measurement
EFO:0010410	triacylglycerol 50:3 measurement

MeSH disease descriptors (12)

Descriptor	Name	Tree numbers
D003110	Colonic Neoplasms	C04.588.274.476.411.307.180; C06.301.371.411.307.180; C06.405.249.411.307.180; C06.405.469.158.356.180; C06.405.469.491.307.180
D003704	Dementia	C10.228.140.380; F03.615.400
D003866	Depressive Disorder	F03.600.300
D020821	Dystonic Disorders	C10.228.662.300
D057090	Eccrine Porocarcinoma	C04.557.470.200.025.500
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D020734	Parkinsonian Disorders	C10.228.140.079.862; C10.228.662.600
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C565779	Ataxia Telangiectasia Like Disorder (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3308929 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
MRE11 Frameshift	Olaparib	Prostate Cancer	Sensitivity/Response	CIViC B	EID1016
MRE11 Loss	Talazoparib	Endometrial Cancer	Sensitivity/Response	CIViC D	EID876

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

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-(3H-benzimidazol-5-yl)-2-cyano-N-(4-phenyl-1,3-thiazol-2-yl)propanamide	IC50	50000 nM	US-11453663: Substituted propanamides as inhibitors of nucleases

ChEMBL bioactivities

56 potent at pChembl≥5 of 77 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.70	IC50	200	nM	CHEMBL6163352
6.52	IC50	300	nM	CHEMBL6165723
6.40	IC50	400	nM	CHEMBL6168876
6.22	IC50	600	nM	CHEMBL6162618
6.16	IC50	700	nM	CHEMBL6151731
6.10	IC50	800	nM	CHEMBL6147664
6.00	IC50	1000	nM	CHEMBL6143243
5.96	IC50	1100	nM	CHEMBL6162300
5.92	IC50	1200	nM	CHEMBL6163199
5.89	IC50	1300	nM	CHEMBL6163101
5.89	IC50	1300	nM	CHEMBL6170447
5.85	IC50	1400	nM	CHEMBL6148412
5.80	IC50	1600	nM	CHEMBL6149785
5.68	IC50	2100	nM	CHEMBL6148530
5.68	IC50	2100	nM	CHEMBL6143926
5.60	IC50	2500	nM	CHEMBL6150580
5.59	Kd	2590	nM	CHEMBL3752910
5.59	ED50	2590	nM	CHEMBL3752910
5.58	IC50	2600	nM	CHEMBL6170312
5.57	IC50	2700	nM	CHEMBL5977046
5.50	IC50	3200	nM	CHEMBL6030155
5.48	IC50	3300	nM	CHEMBL6120904
5.48	IC50	3300	nM	CHEMBL6170744
5.47	IC50	3400	nM	CHEMBL5965552
5.37	Kd	4300	nM	CHEMBL5400171
5.22	IC50	6000	nM	CHEMBL5909125
5.22	IC50	6000	nM	CHEMBL5965552
5.22	IC50	6000	nM	CHEMBL5926888
5.22	IC50	6000	nM	CHEMBL5807217
5.22	IC50	6000	nM	CHEMBL5957100
5.22	IC50	6000	nM	CHEMBL5980711
5.22	IC50	6000	nM	CHEMBL6000047
5.22	IC50	6000	nM	CHEMBL5998280
5.22	IC50	6000	nM	CHEMBL5776329
5.22	IC50	6000	nM	CHEMBL5900522
5.22	IC50	6000	nM	CHEMBL6030155
5.22	IC50	6000	nM	CHEMBL6035385
5.22	IC50	6000	nM	CHEMBL5992370
5.22	IC50	6000	nM	CHEMBL5785957
5.22	IC50	6000	nM	CHEMBL5835280
5.22	IC50	6000	nM	CHEMBL5759709
5.22	IC50	6000	nM	CHEMBL5811055
5.22	IC50	6000	nM	CHEMBL5777581
5.22	IC50	6000	nM	CHEMBL5977046
5.22	IC50	6000	nM	CHEMBL5887710
5.22	IC50	6000	nM	CHEMBL5759755
5.22	IC50	6000	nM	CHEMBL5911606
5.22	IC50	6000	nM	CHEMBL5824471
5.22	IC50	6000	nM	CHEMBL5805125
5.22	IC50	6000	nM	CHEMBL6065827

PubChem BioAssay actives

2 with measured affinity, of 11 total; 2 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	2148767: Binding affinity to human MRE11A incubated for 45 mins by Kinobead based pull down assay	kd	2.5903	uM
4-phenyl-1-[2-(3-piperazin-1-ylpropoxy)naphthalen-1-yl]butan-1-one	2034116: Binding affinity to his-tagged recombinant human MRE11 assessed as dissociation constant by MST assay	kd	4.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, increases expression, decreases expression, affects binding	3
bisphenol A	decreases expression	2
sodium arsenite	decreases expression, increases abundance	2
zinc chromate	increases expression, affects expression	2
Doxorubicin	decreases expression	2
Rotenone	decreases expression, increases expression	2
Valproic Acid	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
pradimicin-IRD	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
lasiocarpine	decreases expression, increases metabolic processing	1
myristicin	decreases expression	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
decabromobiphenyl ether	increases expression	1
riddelliine	increases metabolic processing, decreases expression	1
bromoacetate	increases expression	1
tetrabromobisphenol A	increases expression	1
doxifluridine	decreases response to substance	1
manganese chloride	increases abundance, increases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
1-UFT protocol	decreases response to substance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	affects expression	1
azoxystrobin	decreases expression	1

ChEMBL screening assays

36 unique, capped per target: 36 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1220153	Binding	Inhibition of human Mre11 nuclease activity at 100 uM	A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex. — Nat Chem Biol

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 1 finite cell line, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_6303	KAT-18	Cancer cell line	Sex unspecified
CVCL_B8KS	Abcam HCT 116 MRE11 KO	Cancer cell line	Male
CVCL_B8Z1	Abcam MCF-7 MRE11 KO	Cancer cell line	Female
CVCL_E0ID	Ubigene HeLa MRE11 KO	Cancer cell line	Female
CVCL_KT76	HeLa SilenciX MRE11	Cancer cell line	Female
CVCL_VL02	AT-LD2	Finite cell line	Male
CVCL_VL03	AT-LD2-hTERT	Telomerase immortalized cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00014638	PHASE4	COMPLETED	Letrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
NCT00022386	PHASE4	COMPLETED	Epoetin Alfa in Treating Chemotherapy-Related Anemia in Women With Stage I, Stage II, or Stage III Breast Cancer
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00082277	PHASE4	COMPLETED	Anastrozole Biphosphonate Study in Postmenopausal Women With Hormone-Receptor-Positive Early Breast Cancer
NCT00087620	PHASE4	TERMINATED	A Study of Capecitabine In Combination With Docetaxel vs Capecitabine Followed by Docetaxel As First-Line Treatment For Metastatic Breast Cancer
NCT00121836	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) in Women With HER2-Negative Metastatic Breast Cancer
NCT00126360	PHASE4	UNKNOWN	STARS Breast Trial (Study of Anastrozole and Radiotherapy Sequencing Pilot)
NCT00127933	PHASE4	COMPLETED	XeNA Study - A Study of Xeloda (Capecitabine) in Patients With Invasive Breast Cancer
NCT00128297	PHASE4	COMPLETED	Pamidronate Administration in Breast Cancer Patients With Bone Metastases
NCT00129597	PHASE4	UNKNOWN	Effect of Ketalar to Prevent Postoperative Chronic Pain After Mastectomy
NCT00131170	PHASE4	COMPLETED	Paravertebral Block for Breast Surgery
NCT00156039	PHASE4	COMPLETED	Randomized Trial of Follow-up Strategies in Breast Cancer
NCT00160901	PHASE4	COMPLETED	Complementary Therapies for the Reduction of Side Effects During Chemotherapy for Breast Cancer
NCT00171847	PHASE4	TERMINATED	Study of the Efficacy and Safety of Letrozole Combined With Trastuzumab in Patients With Metastatic Breast Cancer
NCT00176046	PHASE4	COMPLETED	Mistletoe Extract in Early or Advanced Breast Cancer, A Feasibility Study
NCT00190697	PHASE4	COMPLETED	A Study of LY353381 (Arzoxifene) for Patients Who Benefitted From This Drug in Other Oncology Trials and Wished to Continue Treatment
NCT00234195	PHASE4	COMPLETED	Wellbutrin XL, Major Depressive Disorder and Breast Cancer
NCT00237133	PHASE4	COMPLETED	Treatment of Locally Advanced Breast Cancer With Letrozole in Postmenopausal Women
NCT00237224	PHASE4	COMPLETED	Open Label Study of Postmenopausal Women With ER and /or PgR Positive Breast Cancer Treated With Letrozole
NCT00241046	PHASE4	TERMINATED	Letrozole in the Treatment of 1st and 2nd Line Hormone Receptor Positive Breast Cancer: Pre-therapeutic Risk Assessment
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00323479	PHASE4	COMPLETED	Arthralgia During Anastrozole Therapy for Breast Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00356148	PHASE4	COMPLETED	The Efficacy of Prophylactic Antibiotic Administration During Breast Cancer Surgery in Overweight Patients.
NCT00372476	PHASE4	COMPLETED	Efficacy and Safety of Imatinib and Vinorelbine in Patients With Advanced Breast Cancer
NCT00413491	PHASE4	UNKNOWN	National Screening in Denmark With MR Versus Mammography and Ultrasound of Women With BRCA1 or BRCA2 Mutations
NCT00484614	PHASE4	UNKNOWN	Study the Role of Positron Emission Mammography in Pre-surgical Planning for Breast Cancer
NCT00485953	PHASE4	COMPLETED	Effect of Bisphosphonate on Bone Loss in Postmenopausal Women With Breast Cancer Initiating Aromatase Inhibitor Therapy
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00531973	PHASE4	UNKNOWN	A Study of Liposomal Doxorubicin in Women With Breast Cancer Exploiting Tissue Doppler Imaging
NCT00537771	PHASE4	COMPLETED	Liver Safety Under Upfront Arimidex vs Tamoxifen
NCT00544986	PHASE4	COMPLETED	A Prospective,Open-label Study of Anastrozole in Post-menopausal Women With Hormone Sensitive Advanced Breast Cancer
NCT00613275	PHASE4	COMPLETED	Patient Navigation in the Safety Net:CONNECTeDD
NCT00638599	PHASE4	COMPLETED	Comparison of Laryngeal Mask Airway (LMA®) and Tracheal Tube in Modified Radical Mastectomy on Breast Cancer
NCT00647075	PHASE4	UNKNOWN	Yunzhi as Dietary Supplement in Breast Cancer
NCT00688909	PHASE4	COMPLETED	Rheumatological Evaluation of Anastrozole and Letrozole as Adjuvant Treatment in Post-menopausal Women With Breast Cancer
NCT00699101	PHASE4	TERMINATED	Using the Conture® Multi-Lumen Balloon to Deliver Accelerated Partial Breast Brachytherapy
NCT00742222	PHASE4	COMPLETED	Electronic Xoft Intersociety Brachytherapy Trial: Electronic Brachytherapy (EBT) For Treatment of Early Stage Breast Cancer
NCT00754767	PHASE4	TERMINATED	L-Carnitine L-Tartrate in Preventing Peripheral Neuropathy Caused By Chemotherapy in Women With Metastatic Breast Cancer