MAD2L2

Summary

MAD2L2 (mitotic arrest deficient 2 like 2, HGNC:6764) is a protein-coding gene on chromosome 1p36.22, encoding Mitotic spindle assembly checkpoint protein MAD2B (Q9UI95). Adapter protein able to interact with different proteins and involved in different biological processes. It is a selective cancer dependency (DepMap: 89.2% of cell lines).

The protein encoded by this gene is a component of the mitotic spindle assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. The encoded protein, which is similar to MAD2L1, is capable of interacting with ADAM9, ADAM15, REV1, and REV3 proteins.

Source: NCBI Gene 10459 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Fanconi anemia (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 183 total — 1 pathogenic
• Phenotypes (HPO): 112
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 89.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006341

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6764
Approved symbol	MAD2L2
Name	mitotic arrest deficient 2 like 2
Location	1p36.22
Locus type	gene with protein product
Status	Approved
Aliases	MAD2B, REV7, POLZ2, FANCV
Ensembl gene	ENSG00000116670
Ensembl biotype	protein_coding
OMIM	604094
Entrez	10459

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 43 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000235310, ENST00000376655, ENST00000376664, ENST00000376667, ENST00000376669, ENST00000376672, ENST00000376692, ENST00000445656, ENST00000456915, ENST00000697272, ENST00000697273, ENST00000697274, ENST00000717649, ENST00000856191, ENST00000856192, ENST00000856193, ENST00000856194, ENST00000856195, ENST00000911690, ENST00000911691, ENST00000911692, ENST00000911693, ENST00000911694, ENST00000911695, ENST00000911696, ENST00000911697, ENST00000911698, ENST00000911699, ENST00000911700, ENST00000911701, ENST00000911702, ENST00000911703, ENST00000911704, ENST00000911705, ENST00000911706, ENST00000911707, ENST00000911708, ENST00000911709, ENST00000911710, ENST00000911711, ENST00000911712, ENST00000911713, ENST00000911714, ENST00000911715, ENST00000911716, ENST00000911717, ENST00000954011, ENST00000954012

RefSeq mRNA: 2 — MANE Select: NM_006341 NM_001127325, NM_006341

CCDS: CCDS134

Canonical transcript exons

ENST00000376692 — 9 exons

Exon	Start	End
ENSE00001698714	11681039	11681148
ENSE00003511603	11677543	11677614
ENSE00003611733	11680562	11680613
ENSE00003641668	11676848	11676948
ENSE00003664098	11680353	11680471
ENSE00003889074	11675082	11675174
ENSE00003890407	11676046	11676140
ENSE00003894266	11674480	11674816
ENSE00003970113	11675658	11675731

Expression profiles

Bgee: expression breadth ubiquitous, 229 present calls, max score 96.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.1772 / max 223.6468, expressed in 1814 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10303	22.1094	1812
10307	3.4081	502
10302	2.7293	998
10309	0.8338	205
10308	0.5720	257
10306	0.3619	171
201351	0.0912	36
10304	0.0418	8
10305	0.0296	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
embryo	UBERON:0000922	96.65	gold quality
ganglionic eminence	UBERON:0004023	96.65	gold quality
left testis	UBERON:0004533	95.54	gold quality
right testis	UBERON:0004534	95.45	gold quality
granulocyte	CL:0000094	93.29	gold quality
testis	UBERON:0000473	93.28	gold quality
cortical plate	UBERON:0005343	93.28	gold quality
gastrocnemius	UBERON:0001388	92.67	gold quality
stromal cell of endometrium	CL:0002255	92.35	gold quality
ventricular zone	UBERON:0003053	92.23	gold quality
muscle of leg	UBERON:0001383	92.20	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.82	gold quality
right lobe of liver	UBERON:0001114	91.72	gold quality
body of pancreas	UBERON:0001150	91.67	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.56	gold quality
cartilage tissue	UBERON:0002418	91.38	gold quality
apex of heart	UBERON:0002098	91.06	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.81	gold quality
body of stomach	UBERON:0001161	90.72	gold quality
cerebellar hemisphere	UBERON:0002245	90.64	gold quality
cerebellar cortex	UBERON:0002129	90.58	gold quality
tibial nerve	UBERON:0001323	90.28	gold quality
lower esophagus muscularis layer	UBERON:0035833	89.93	gold quality
mucosa of stomach	UBERON:0001199	89.92	gold quality
lower esophagus	UBERON:0013473	89.89	gold quality
pancreas	UBERON:0001264	89.82	gold quality
tibialis anterior	UBERON:0001385	89.70	silver quality
caudate nucleus	UBERON:0001873	89.70	gold quality
leukocyte	CL:0000738	89.60	gold quality
islet of Langerhans	UBERON:0000006	89.58	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-9388	yes	1136.24
E-CURD-112	yes	45.02
E-HCAD-10	yes	24.38
E-MTAB-9067	yes	16.64
E-CURD-114	yes	6.70
E-ANND-3	yes	6.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting MAD2L2, 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-4524A-3P	99.72	66.85	2406
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-194-3P	97.36	65.96	1027

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 89.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• purified human REV1 and REV7 proteins form a heterodimer in solution, which is stable through intensive purification steps. (PMID:12529368)
• Upregulated MAD2L2 expression is associated with colorectal tumors (PMID:17044027)
• Human Rev7 (hRev7)/MAD2B/MAD2L2 is an interaction partner for Elk-1 and hRev7 acts to promote Elk-1 phosphorylation by the c-Jun N-terminal protein kinase (JNK) MAP kinases. (PMID:17296730)
• Chromophobe renal cell carcinoma presented underexpression of MAD1, and MAD2L2. (PMID:17333263)
• Hepatocellular carcinoma-associated gene 2 interacts with MAD2L2. (PMID:17541814)
• Rev7 is essential for mutagenesis and S phase progression in UV-irradiated fibroblasts. (PMID:18295554)
• Study provides the first evidence for the involvement of MAD2B in TCF4-mediated epithelial-mesenchymal transdifferentiation. (PMID:19443654)
• the small GTPase RAN is a novel MAD2B binding protein (PMID:19753112)
• To clarify the structural basis of the interaction between REV7 and REV3, REV7 was crystallized in complex with a REV3 fragment. (PMID:20054135)
• hMAD2 also binds to the hREV7-binding sequence in hREV3, whereas hMAD2 does not bind to a similar sequence in ADAM9 or ELK-1 and hREV7 does not bind to the hMAD2-binding sequence in hMAD1 or hCDC20. (PMID:20088965)
• show the first crystal structure of REV7 in complex with a fragment of REV3 polymerase (residues 1847-1898) and reveal the mechanism underlying REV7-REV3 interaction (PMID:20164194)
• The hRev7 is required for TLS past BPDE-induced DNA lesions but that it is not essential for inserting nucleotides opposite such lesions suggest a role for hPolzeta in the extension step of translesion synthesis. (PMID:21143968)
• Data show that MAD2B interacts with CLTA during the G2/M phase of the cell cycle and that depletion of MAD2B leads to a marked increase in the percentage of misaligned chromosomes and a redistribution of CLTA during mitosis. (PMID:21152103)
• The REV1/Polzeta complex maintains genomic stability by directly participating in DNA double-stranded break repair. (PMID:21926160)
• MAD2B may mediate Sim2 function during development in CNS and thereby play a critical role in pathophysiological mechanisms in Down syndrome (PMID:22660985)
• the Rev1 C-terminal domain utilizes independent interaction interfaces to simultaneously bind a fragment of the ‘inserter’ poleta and Rev7 subunit of the ’extender’ polvarsigma, thereby serving as a cassette that may accommodate several polymerases (PMID:22828282)
• analysis of the crystal structure of the ternary complex composed of the C-terminal domain of human REV1, REV7, and a REV3 fragment (PMID:22859296)
• ternary complex of the C-terminal domain of human REV1 in complex with REV7 bound to a REV3 fragment has been crystallized. The crystals belonged to space group P3(1)21, with unit-cell parameters a = b = 74.7, c = 124.5 A (PMID:22869133)
• REV7 is required for anaphase-promoting complex-dependent ubiquitination and degradation of translesion DNA polymerase REV1. (PMID:23287467)
• MAD2L2 helps to ensure a robustly bistable switch between APC/C(CDC20) and APC/C(CDH1) during the metaphase-to-anaphase transition, thereby contributing to mitotic fidelity. (PMID:24100295)
• These findings indicate that depletion of REV7 enhances sensitivity to cisplatin treatment in ovarian clear cell carcinoma (CCC), suggesting that REV7 is a candidate molecular target in CCC management. (PMID:24597627)
• that MAD2B may play an important role in high glucose-mediated podocyte injury of diabetic nephropathy via modulation of Cdh1, cyclin B1, and Skp2 expression (PMID:25651564)
• data establish MAD2L2 as a crucial contributor to the control of DNA repair activity by 53BP1 that promotes NHEJ by inhibiting 5’ end resection downstream of RIF1 (PMID:25799990)
• results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells (PMID:25799992)
• Skp2, a confirmed APC/C-CDH1 substrate and E-cadherin destroyer, was increased in TGF-beta1-treated proximal tubular epithelial cells, which could be blocked by MAD2B depletion. (PMID:27488450)
• REV7 is a previously undescribed FA gene, which we term FANCV (PMID:27500492)
• structure-based interaction analyses revealed an unprecedented mechanism involving CAMP’s WK motif. Surprisingly, in one of the crystal forms, the MAD2L2-CAMP complex formed a dimeric structure in which the C-terminal region of MAD2L2 was swapped and adopted an immature structure (PMID:28887307)
• Our study showed that MAD2B expression significantly increased in lung cancer, especially in the metastatic tissues.. these findings indicate an oncogenic role of MAD2B in lung cancer, and slug might be involved in the process. (PMID:28899455)
• Mechanistically, MAD2B physically interacted with TCF4 to repress TCF4 transcriptional activity via beta-catenin mediation, leading to reduced beta-catenin/TCF4-dependent transactivation and Wnt signaling activity. These results demonstrate, for the first time, that MAD2B plays a negative role in TCF4-induced dermal papilla cell growth and proliferation. (PMID:28916740)
• the differential H4K20 methylation status between pre-replicative and post-replicative DNA represents an intrinsic mechanism that locally ensures appropriate recruitment of the 53BP1-RIF1-MAD2L2 complex at DNA double strand breaks. (PMID:29160738)
• Increased MAD2L2 expression in colorectal cancer cells activated p38, which was required for the phosphorylation of NCOA3 that led to its ubiquitination and degradation by the proteasome. (PMID:29360267)
• found FAM35A, a previously unstudied protein with an unstructured N-terminal region and a C-terminal region harboring three OB-fold domains similar to single-stranded DNA-binding protein RPA, as novel interactor of REV7/RIF1/53BP1. (PMID:29789392)
• results provide insights into the structure of the Rev1/Polzeta TLS assembly and highlight the function of Rev7 homo- and heterodimerization. (PMID:30111544)
• these results establish SHLD2 as a novel effector of REV7 in controlling the decision-making process during DSB repair. (PMID:30154076)
• REV7-PRDX2 complex also assembled onto DNA double-strand breaks. (PMID:30657231)
• REV7 preferentially binds GTP-bound RAN, implying that a GTP/GDP-bound transition of RAN may serve as the molecular switch that controls REV7’s activity. (PMID:31484720)
• Structural basis for shieldin complex subunit 3-mediated recruitment of the checkpoint protein REV7 during DNA double-strand break repair. (PMID:31796627)
• Inactivation of REV7 enhances chemosensitivity and overcomes acquired chemoresistance in testicular germ cell tumors. (PMID:32553781)
• CDH1 binds MAD2L2 in a Rev1-like pattern. (PMID:32811646)
• MDA-MB-157 Cell Line Presents High Levels of MAD2L2 and Dysregulated Mitosis. (PMID:32988869)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mad2l2	ENSDARG00000042456
mus_musculus	Mad2l2	ENSMUSG00000029003
rattus_norvegicus	Mad2l2	ENSRNOG00000009134
drosophila_melanogaster	PolZ2	FBGN0037345

Paralogs (1): MAD2L1 (ENSG00000164109)

Protein

Protein identifiers

Mitotic spindle assembly checkpoint protein MAD2B — Q9UI95 (reviewed: Q9UI95)

Alternative names: Mitotic arrest deficient 2-like protein 2, REV7 homolog

All UniProt accessions (7): Q9UI95, A0A8V8TKV6, A0A8V8TL87, A0A8V8TMF5, B1AK43, B1AK44, B1AK45

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein able to interact with different proteins and involved in different biological processes. Mediates the interaction between the error-prone DNA polymerase zeta catalytic subunit REV3L and the inserter polymerase REV1, thereby mediating the second polymerase switching in translesion DNA synthesis. Translesion DNA synthesis releases the replication blockade of replicative polymerases, stalled in presence of DNA lesions. Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs). During G1 and S phase of the cell cycle, the complex functions downstream of TP53BP1 to promote non-homologous end joining (NHEJ) and suppress DNA end resection. Mediates various NHEJ-dependent processes including immunoglobulin class-switch recombination, and fusion of unprotected telomeres. May also regulate another aspect of cellular response to DNA damage through regulation of the JNK-mediated phosphorylation and activation of the transcriptional activator ELK1. Inhibits the FZR1- and probably CDC20-mediated activation of the anaphase promoting complex APC thereby regulating progression through the cell cycle. Regulates TCF7L2-mediated gene transcription and may play a role in epithelial-mesenchymal transdifferentiation.

Subunit / interactions. Homooligomer. Heterodimer with REV3L. This dimer forms the minimal DNA polymerase zeta complex (Pol-zeta2), with REV3L bearing DNA polymerase catalytic activity, although its activity is very low in this context. Component of the tetrameric Pol-zeta complex (Pol-zeta4), which consists of REV3L, MAD2L2, POLD2 and POLD3; Pol-zeta4 is the fully active form of DNA polymerase zeta. Component of the shieldin complex, consisting of SHLD1, SHLD2, SHLD3 and MAD2L2/REV7. Within the complex, SHLD2 forms a scaffold which interacts with a SHLD3-MAD2L2 subcomplex via its N-terminus, and with SHLD1 via its C-terminus. Interacts with REV1. Interacts with ADAM9. Interacts with CHAMP1. Interacts with FZR1 (in complex with the anaphase promoting complex APC). Interacts with CDC20; PubMed:11459825 could not detect the interaction. Interacts with RAN. Interacts with ELK1; the interaction is direct and recruits MAD2L2 to ELK1-specific promoters. May interact with the JNK kinases MAPK8 and/or MAPK9 to stimulate ELK1 phosphorylation and transcriptional activity upon DNA damage. Interacts with TCF7L2; prevents its binding to promoters and negatively modulates its transcriptional activity. Interacts with YY1AP1. Interacts with S.flexneri protein ipaB; prevents the interaction of MAD2L2 with FZR1 and CDC20 resulting in an activation of the anaphase-promoting complex APC and a cell cycle arrest. Interacts with PRCC; the interaction is direct. Interacts with POGZ. Interacts with ASTE1. Forms a quaternary complex with POLK, REV1 and REV3L, where REV3L-bound MAD2L2 and POLK are able to bind simultaneously to REV1 forming the stable translesion synthesis (TLS) machinery therefore bridging the inserter and extender polymerases.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Spindle. Chromosome.

Tissue specificity. Ubiquitously expressed.

Disease relevance. Fanconi anemia, complementation group V (FANCV) [MIM:617243] A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (2): NP_001120797, NP_006332* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003511	HORMA_dom	Domain
IPR036570	HORMA_dom_sf	Homologous_superfamily
IPR045091	Mad2-like	Family

Pfam: PF02301

UniProt features (36 total): strand 11, helix 9, mutagenesis site 6, sequence conflict 3, region of interest 2, turn 2, chain 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

24 structures.

PDB	Method	Resolution (Å)
6BCD	X-RAY DIFFRACTION	1.43
6BC8	X-RAY DIFFRACTION	1.68
6M7B	X-RAY DIFFRACTION	1.77
3ABD	X-RAY DIFFRACTION	1.9
4EXT	X-RAY DIFFRACTION	1.9
6M7A	X-RAY DIFFRACTION	1.9
6VE5	X-RAY DIFFRACTION	2
6NIF	X-RAY DIFFRACTION	2
5XPT	X-RAY DIFFRACTION	2.1
6K07	X-RAY DIFFRACTION	2.24
6WS0	X-RAY DIFFRACTION	2.24
5XPU	X-RAY DIFFRACTION	2.3
6K08	X-RAY DIFFRACTION	2.31
6KEA	X-RAY DIFFRACTION	2.35
6WS5	X-RAY DIFFRACTION	2.47
3ABE	X-RAY DIFFRACTION	2.6
4GK0	X-RAY DIFFRACTION	2.7
6WW9	X-RAY DIFFRACTION	2.7
3VU7	X-RAY DIFFRACTION	2.8
6BI7	X-RAY DIFFRACTION	2.8
4GK5	X-RAY DIFFRACTION	3.21
6KTO	X-RAY DIFFRACTION	3.45
7L9P	ELECTRON MICROSCOPY	3.6
6WWA	X-RAY DIFFRACTION	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UI95-F1	90.73	0.74

Functional residue map

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

Mutagenesis-validated functional residues (6):

Position	Phenotype
202	significantly prevents interaction with rev1; no effect on interaction with rev3l.
63	alters interaction with rev3l. loss of interaction with rev3l; when associated with a-171.
124	induces structural changes that increase affinity for rev3l and rev1. no effect on interaction with rev1; when associate
171	alters interaction with rev3l and rev1. loss of interaction with rev3l; when associated with a-63. no effect on interact
186	significantly prevents interaction with rev1; no effect on interaction with rev3l.
200	significantly prevents interaction with rev1; no effect on interaction with rev3l.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-110312	Translesion synthesis by REV1
R-HSA-5655862	Translesion synthesis by POLK
R-HSA-5656121	Translesion synthesis by POLI
R-HSA-110313	Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template
R-HSA-73893	DNA Damage Bypass
R-HSA-73894	DNA Repair

MSigDB gene sets: 539 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, HONMA_DOCETAXEL_RESISTANCE, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GOBP_B_CELL_ACTIVATION, GOBP_REGULATION_OF_CELL_CELL_ADHESION_MEDIATED_BY_CADHERIN, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_DNA_REPAIR, GOBP_PEPTIDYL_SERINE_MODIFICATION, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN

GO Biological Process (25): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of cell growth (GO:0001558), somatic diversification of immunoglobulins involved in immune response (GO:0002208), DNA repair (GO:0006281), double-strand break repair (GO:0006302), actin filament organization (GO:0007015), mitotic spindle assembly checkpoint signaling (GO:0007094), negative regulation of epithelial to mesenchymal transition (GO:0010719), obsolete negative regulation of transcription by competitive promoter binding (GO:0010944), translesion synthesis (GO:0019985), positive regulation of peptidyl-serine phosphorylation (GO:0033138), negative regulation of protein catabolic process (GO:0042177), error-prone translesion synthesis (GO:0042276), DNA damage response, signal transduction resulting in transcription (GO:0042772), telomere maintenance in response to DNA damage (GO:0043247), positive regulation of isotype switching (GO:0045830), positive regulation of DNA-templated transcription (GO:0045893), cell division (GO:0051301), negative regulation of canonical Wnt signaling pathway (GO:0090090), negative regulation of ubiquitin protein ligase activity (GO:1904667), negative regulation of double-strand break repair via homologous recombination (GO:2000042), negative regulation of cell-cell adhesion mediated by cadherin (GO:2000048), positive regulation of double-strand break repair via nonhomologous end joining (GO:2001034), DNA damage response (GO:0006974), regulation of epithelial to mesenchymal transition (GO:0010717)

GO Molecular Function (5): transcription corepressor activity (GO:0003714), JUN kinase binding (GO:0008432), protein-macromolecule adaptor activity (GO:0030674), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein binding (GO:0005515)

GO Cellular Component (11): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), cytoplasm (GO:0005737), spindle (GO:0005819), zeta DNA polymerase complex (GO:0016035), site of double-strand break (GO:0035861), site of DNA damage (GO:0090734), anaphase-promoting complex (GO:0005680), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	3
DNA Damage Bypass	1
DNA Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular membraneless organelle	3
negative regulation of DNA-templated transcription	2
DNA damage response	2
chromosome	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
immunoglobulin production involved in immunoglobulin-mediated immune response	1
somatic diversification of immunoglobulins	1
DNA metabolic process	1
DNA repair	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
mitotic cell cycle	1
negative regulation of mitotic metaphase/anaphase transition	1
spindle assembly checkpoint signaling	1
mitotic spindle checkpoint signaling	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
negative regulation of cell differentiation	1
negative regulation of multicellular organismal process	1
DNA damage tolerance	1
DNA synthesis involved in DNA replication	1
positive regulation of protein phosphorylation	1
peptidyl-serine phosphorylation	1
regulation of peptidyl-serine phosphorylation	1
negative regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
negative regulation of protein metabolic process	1
translesion synthesis	1
signal transduction in response to DNA damage	1
telomere maintenance	1
positive regulation of immunoglobulin production	1
positive regulation of immunoglobulin mediated immune response	1
isotype switching	1
regulation of isotype switching	1

Protein interactions and networks

STRING

1458 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAD2L2	REV3L	O60673	999
MAD2L2	REV1	Q9UBZ9	999
MAD2L2	SHLD2	Q86V20	996
MAD2L2	SHLD1	Q8IYI0	996
MAD2L2	POLD2	P49005	991
MAD2L2	SHLD3	Q6ZNX1	981
MAD2L2	POLD3	Q15054	973
MAD2L2	PAXIP1	Q6ZW49	930
MAD2L2	TP53BP1	Q12888	904
MAD2L2	ADAM9	Q13443	859
MAD2L2	CDC20	Q12834	832
MAD2L2	POLH	Q9Y253	811
MAD2L2	RAD51	Q06609	797
MAD2L2	POLM	Q9NP87	788
MAD2L2	HORMAD1	Q86X24	782

IntAct

207 interactions, top by confidence:

A	B	Type	Score
CHAMP1	MAD2L2	psi-mi:“MI:0915”(physical association)	0.820
HLA-C	HLA-A	psi-mi:“MI:0914”(association)	0.670
SHLD3	MAD2L2	psi-mi:“MI:0915”(physical association)	0.650
SHLD3	MAD2L2	psi-mi:“MI:0407”(direct interaction)	0.650
SHLD3	MAD2L2	psi-mi:“MI:0403”(colocalization)	0.650
MAD2L2	REV3L	psi-mi:“MI:0915”(physical association)	0.640
MAD2L2	REV3L	psi-mi:“MI:0407”(direct interaction)	0.640
MAD2L2	ADAM9	psi-mi:“MI:0915”(physical association)	0.630
MAD2L2	sctE	psi-mi:“MI:0915”(physical association)	0.600
sctE	MAD2L2	psi-mi:“MI:0915”(physical association)	0.600
MAD2L2	sctE	psi-mi:“MI:0403”(colocalization)	0.600
MAD2L2	SFI1	psi-mi:“MI:0915”(physical association)	0.560
MAD2L2	TRIM27	psi-mi:“MI:0915”(physical association)	0.560
TCF4	MAD2L2	psi-mi:“MI:0915”(physical association)	0.560
MAD2L2	REL	psi-mi:“MI:0915”(physical association)	0.560
MAD2L2	IKZF1	psi-mi:“MI:0915”(physical association)	0.560
CAMK2B	MAD2L2	psi-mi:“MI:0915”(physical association)	0.560
KCTD9	MAD2L2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (618): MAD2L2 (Two-hybrid), MAD2L2 (Two-hybrid), MAD2L2 (Two-hybrid), MAD2L2 (Two-hybrid), MAD2L2 (Two-hybrid), MAD2L2 (Two-hybrid), KCTD9 (Two-hybrid), MAD2L2 (Affinity Capture-RNA), MAD2L2 (Affinity Capture-RNA), MAD2L2 (Affinity Capture-MS), CBX3 (Affinity Capture-MS), CHAMP1 (Affinity Capture-MS), POGZ (Affinity Capture-MS), GTF2I (Affinity Capture-MS), CBX5 (Affinity Capture-MS)

ESM2 similar proteins: A0MQH0, A4IFQ0, A6QR06, A9UHW6, D3Z8D9, P83900, Q13769, Q25BN1, Q28H85, Q2KIP7, Q3ZC21, Q4KWZ6, Q568H3, Q5BJQ7, Q5F415, Q5R372, Q5R8I6, Q5RCW6, Q5RDB9, Q62784, Q68FX7, Q6TUI4, Q6TV19, Q6ZPY2, Q8BKT7, Q8BPU7, Q8C0Q9, Q8CIQ7, Q8IUI8, Q8IZD9, Q8K0F1, Q8NCR0, Q8QFR4, Q8R418, Q91YQ7, Q92556, Q92565, Q96BN2, Q96G75, Q96PE3

Diamond homologs: D3Z8D9, Q0E7J8, Q28H85, Q2KIP7, Q4KWZ6, Q54S00, Q568H3, Q8QFR4, Q94FL5, Q9D752, Q9UI95, Q59VQ3, Q9VNE1

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PRCC	up-regulates	MAD2L2	relocalization
CHAMP1	“up-regulates activity”	MAD2L2	binding
MAD2L2	“down-regulates activity”	FZR1	binding
MAD2L2	“down-regulates activity”	CDC20	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 126 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
APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1	6	14.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	73
Likely benign	94
Benign	8

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
372196	NM_006341.4(MAD2L2):c.254T>A (p.Val85Glu)	Pathogenic

SpliceAI

3383 predictions. Top by Δscore:

Variant	Effect	Δscore
1:11658262:A:AG	acceptor_gain	1.0000
1:11658263:T:G	acceptor_gain	1.0000
1:11658265:A:AG	acceptor_gain	1.0000
1:11658265:A:AT	acceptor_loss	1.0000
1:11658265:AGAG:A	acceptor_gain	1.0000
1:11658265:AGAGG:A	acceptor_gain	1.0000
1:11658266:G:GG	acceptor_gain	1.0000
1:11658266:GA:G	acceptor_gain	1.0000
1:11658266:GAGG:G	acceptor_gain	1.0000
1:11658266:GAGGG:G	acceptor_gain	1.0000
1:11658343:G:GT	donor_gain	1.0000
1:11658362:CAGG:C	donor_loss	1.0000
1:11658363:AG:A	donor_loss	1.0000
1:11658365:GTCA:G	donor_loss	1.0000
1:11658394:G:GG	donor_gain	1.0000
1:11658624:GACTG:G	donor_gain	1.0000
1:11658626:CTG:C	donor_gain	1.0000
1:11658627:TG:T	donor_gain	1.0000
1:11658627:TGGT:T	donor_loss	1.0000
1:11658628:GG:G	donor_gain	1.0000
1:11658628:GGT:G	donor_loss	1.0000
1:11658629:G:GG	donor_gain	1.0000
1:11658629:GTG:G	donor_loss	1.0000
1:11658630:T:G	donor_loss	1.0000
1:11658631:GAGT:G	donor_loss	1.0000
1:11658733:CA:C	acceptor_loss	1.0000
1:11658734:A:AG	acceptor_gain	1.0000
1:11658734:AG:A	acceptor_gain	1.0000
1:11658735:G:GT	acceptor_gain	1.0000
1:11658735:GG:G	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000848029 (1:11678381 A>C), RS1000879171 (1:11678921 T>C,G), RS1001096536 (1:11690459 T>C), RS1001124621 (1:11677122 T>C), RS1001196992 (1:11682506 AAAGTAACCTGT>A), RS1001228007 (1:11683209 C>T), RS1001387783 (1:11683304 A>C), RS1001885120 (1:11682820 G>A), RS1002444730 (1:11677869 C>T), RS1002544893 (1:11682516 G>A,T), RS1002723681 (1:11688368 T>A), RS1002732325 (1:11693770 C>T), RS1003056101 (1:11691792 C>T), RS1003340958 (1:11686238 C>A,G,T), RS1003563229 (1:11681561 G>A,C)

Disease associations

OMIM: gene MIM:604094 | disease phenotypes: MIM:617243

GenCC curated gene-disease

Disease	Classification	Inheritance
Fanconi anemia	Supportive	Autosomal recessive
Fanconi anemia complementation group V	Limited	Autosomal recessive

Mondo (3): oligospermia (MONDO:0001913), Fanconi anemia complementation group V (MONDO:0014985), Fanconi anemia (MONDO:0019391)

Orphanet (0):

HPO phenotypes

112 total (30 of 112 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000027	Azoospermia
HP:0000028	Cryptorchidism
HP:0000035	Abnormal testis morphology
HP:0000047	Hypospadias
HP:0000072	Hydroureter
HP:0000079	Abnormality of the urinary system
HP:0000083	Renal insufficiency
HP:0000130	Abnormality of the uterus
HP:0000135	Hypogonadism
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000340	Sloping forehead
HP:0000347	Micrognathia
HP:0000364	Hearing abnormality
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000453	Choanal atresia
HP:0000478	Abnormality of the eye
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000492	Abnormal eyelid morphology
HP:0000504	Abnormality of vision

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001523_32	Visceral adipose tissue adjusted for BMI	1.000000e-06
GCST010654_5	Arterial stiffness (brachial-femoral pulse wave velocity)	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004517	arterial stiffness measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D005199	Fanconi Anemia	C15.378.050.085.080.280; C15.378.190.223.500.500.280; C16.320.077.280; C18.452.284.280
D009845	Oligospermia	C12.100.500.430.508; C12.100.750.700.508; C12.200.294.430.508

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4524021 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2233006	MAD2L2		0.00	0

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation	3
Aflatoxin B1	increases expression, increases methylation	2
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
sodium arsenite	increases expression	1
zinc chromate	decreases expression, increases abundance	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, decreases expression	1
CGP 52608	affects binding, increases reaction	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Chelating Agents	affects binding, affects expression	1
Cisplatin	decreases expression	1
Copper	affects binding, affects expression	1
Coumestrol	increases expression	1
Doxorubicin	decreases expression	1
Fluorouracil	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Nickel	increases expression	1
Ozone	affects expression, increases abundance	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tretinoin	decreases expression	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3858037	Binding	Binding affinity to 5’-MBP-His8/3’-FLAG-tagged REV7 R124A mutant (unknown origin) expressed in Escherichia coli BL21(DE3) at 200 uM by 1H waterLOGSY NMR method	Identification of the first small-molecule inhibitor of the REV7 DNA repair protein interaction. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02307994	PHASE4	UNKNOWN	Clinical Research on Effectiveness and Safety of Treatment of Severe Oligospermia or Azoospermia With uFSH
NCT05320536	PHASE4	UNKNOWN	A Clinical Study of Gulingji Capsule in the Treatment of Idiopathic Oligospermia, Asthenia, and Teratozoospermia
NCT06260007	PHASE4	RECRUITING	Efficacy and Safety Study of Products Based on Tribulus Terrestris, L. in Men With Oligospermia
NCT06519786	PHASE3	UNKNOWN	Safety and Efficacy of Metformin for Treatment of Cytopenia in Children and Adolescents With Fanconi Anemia
NCT00440180	PHASE3	TERMINATED	Aromatase Inhibitors in the Treatment of Male Infertility
NCT00000603	PHASE2	COMPLETED	Cord Blood Stem Cell Transplantation Study (COBLT)
NCT00001749	PHASE2	COMPLETED	Medical Treatment for Diamond Blackfan Anemia
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT00053989	PHASE2	COMPLETED	NMA Allogeneic Hematopoietic Cell Transplant in Hematologic Cancer/Disorders
NCT00084695	PHASE2	UNKNOWN	Umbilical Cord Blood for Stem Cell Transplantation in Treating Young Patients With Malignant or Nonmalignant Diseases
NCT00258427	PHASE2	COMPLETED	Hematopoietic Stem Cell Transplantation in High Risk Patients With Fanconi Anemia
NCT00453388	PHASE2	COMPLETED	Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant, Mycophenolate Mofetil, and Cyclosporine in Treating Patients With Fanconi Anemia
NCT01071239	PHASE2	COMPLETED	Hematopoietic Stem Cell Transplant for Fanconi Anemia
NCT02143830	PHASE2	RECRUITING	HSCT for Patients With Fanconi Anemia Using Risk-Adjusted Chemotherapy
NCT02931071	PHASE2	COMPLETED	Clinical Phase II Trial to Evaluate CD34+ Cells Mobilization and Collection in Patients With Fanconi Anemia for Subsequent Transduction With a Lentiviral Vector Carring FANCA Gene. FANCOSTEM-1
NCT03206086	PHASE2	ACTIVE_NOT_RECRUITING	Eltrombopag for People With Fanconi Anemia
NCT03398824	PHASE2	COMPLETED	Pilot Study of Metformin for Patients With Fanconi Anemia
NCT03476330	PHASE2	COMPLETED	Quercetin Chemoprevention for Squamous Cell Carcinoma in Patients With Fanconi Anemia
NCT03579875	PHASE2	RECRUITING	Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders
NCT03600909	PHASE2	TERMINATED	A Study of the Effect of Blood Stem Cell Transplant After Chemotherapy Alone in Patients With Fanconi Anemia
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT06045052	PHASE2	COMPLETED	Eltrombopag for Treatment of Fanconi Anemia
NCT01409837	PHASE2	COMPLETED	The Effect and Safety of Lisinopril in Non-hypertensive Men With Infertility From Low Sperm Count
NCT02234206	PHASE2	COMPLETED	A Clinical Trial to Study the Safety and Efficacy of Chandrakanthi Choornam in Patients With Low Sperm Count
NCT07481370	PHASE2	ENROLLING_BY_INVITATION	Isotretinoin vs hCG for Male Infertility Due to Low or Absent Sperm
NCT00001399	PHASE1	COMPLETED	Gene Therapy for the Treatment of Fanconi’s Anemia Type C
NCT00005896	PHASE1	UNKNOWN	Phase I Pilot Study of CD34 Enriched, Fanconi’s Anemia Complementation Group C Gene Transduced Autologous Peripheral Blood Stem Cell Transplantation in Patients With Fanconi’s Anemia
NCT00006127	PHASE1	UNKNOWN	Phase I Study of Amifostine in Patients With Bone Marrow Failure Related to Fanconi’s Anemia
NCT00093743	PHASE1	COMPLETED	Low-Dose Total-Body Irradiation and Fludarabine Phosphate Followed by Unrelated Donor Stem Cell Transplant in Treating Patients With Fanconi Anemia
NCT00243399	PHASE1	COMPLETED	Oxandrolone for the Treatment of Bone Marrow Aplasia in Fanconi Anemia
NCT00272857	PHASE1	COMPLETED	Bone Marrow Cell Gene Transfer in Individuals With Fanconi Anemia
NCT00317876	PHASE1	COMPLETED	Cyclophosphamide in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant for Fanconi’s Anemia
NCT00586274	PHASE1	TERMINATED	Use of Rft5-Dga to Deplete Alloreactive Cells for Pts With Fanconi Anemia After Haploidentical SCT
NCT01331018	PHASE1	TERMINATED	Gene Therapy for Fanconi Anemia
NCT01720147	PHASE1	COMPLETED	Quercetin in Children With Fanconi Anemia; a Pilot Study
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT05158114	PHASE1	WITHDRAWN	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for Testicular Injury and Oligospermia
NCT00352976	PHASE2/PHASE3	COMPLETED	TBI Dose De-escalation for Fanconi Anemia
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT00005898	PHASE1/PHASE2	COMPLETED	Phase I/II Study of Total Body Irradiation, Cyclophosphamide, and Fludarabine Followed by Alternate Donor Hematopoietic Cell Transplantation in Patients With Fanconi’s Anemia