MDC1

Summary

MDC1 (mediator of DNA damage checkpoint 1, HGNC:21163) is a protein-coding gene on chromosome 6p21.33, encoding Mediator of DNA damage checkpoint protein 1 (Q14676). Histone reader protein required for checkpoint-mediated cell cycle arrest in response to DNA damage within both the S phase and G2/M phases of the cell cycle.

The protein encoded by this gene contains an N-terminal forkhead domain, two BRCA1 C-terminal (BRCT) motifs and a central domain with 13 repetitions of an approximately 41-amino acid sequence. The encoded protein is required to activate the intra-S phase and G2/M phase cell cycle checkpoints in response to DNA damage. This nuclear protein interacts with phosphorylated histone H2AX near sites of DNA double-strand breaks through its BRCT motifs, and facilitates recruitment of the ATM kinase and meiotic recombination 11 protein complex to DNA damage foci.

Source: NCBI Gene 9656 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 283 total — 3 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_014641

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21163
Approved symbol	MDC1
Name	mediator of DNA damage checkpoint 1
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	NFBD1, KIAA0170, Em:AB023051.5
Ensembl gene	ENSG00000137337
Ensembl biotype	protein_coding
OMIM	607593
Entrez	9656

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000376406, ENST00000416571, ENST00000417033, ENST00000422266, ENST00000425072, ENST00000489540, ENST00000492462, ENST00000494654, ENST00000860518, ENST00000860519, ENST00000939653, ENST00000939654, ENST00000939655, ENST00000939656, ENST00000939657

RefSeq mRNA: 1 — MANE Select: NM_014641 NM_014641

CCDS: CCDS34384

Canonical transcript exons

ENST00000376406 — 15 exons

Exon	Start	End
ENSE00001672479	30711874	30713354
ENSE00001677117	30713648	30713717
ENSE00001680569	30703418	30703537
ENSE00001682597	30707384	30707454
ENSE00001757825	30703621	30706098
ENSE00001773945	30711412	30711504
ENSE00001790042	30707566	30708357
ENSE00001835419	30717245	30717281
ENSE00001891428	30699807	30700632
ENSE00002231208	30713803	30714183
ENSE00002723185	30715040	30715178
ENSE00003506720	30702752	30702877
ENSE00003602749	30711667	30711726
ENSE00003620303	30703104	30703286
ENSE00003633173	30702553	30702663

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 95.12.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.0272 / max 178.9283, expressed in 1730 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72585	9.6954	1702
72586	1.1405	738
72584	0.9861	552
72583	0.2052	103

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	95.12	gold quality
left testis	UBERON:0004533	95.01	gold quality
testis	UBERON:0000473	93.82	gold quality
right lobe of thyroid gland	UBERON:0001119	92.22	gold quality
ventricular zone	UBERON:0003053	92.07	gold quality
left lobe of thyroid gland	UBERON:0001120	91.47	gold quality
right ovary	UBERON:0002118	91.36	gold quality
left ovary	UBERON:0002119	91.22	gold quality
thyroid gland	UBERON:0002046	91.21	gold quality
mucosa of stomach	UBERON:0001199	91.15	gold quality
ovary	UBERON:0000992	90.99	gold quality
body of uterus	UBERON:0009853	90.52	gold quality
pituitary gland	UBERON:0000007	90.07	gold quality
left uterine tube	UBERON:0001303	89.71	gold quality
adenohypophysis	UBERON:0002196	89.66	gold quality
bone marrow cell	CL:0002092	89.19	gold quality
metanephros cortex	UBERON:0010533	89.18	gold quality
tibial nerve	UBERON:0001323	89.12	gold quality
ganglionic eminence	UBERON:0004023	89.06	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	89.05	gold quality
endocervix	UBERON:0000458	88.86	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.85	gold quality
lower esophagus	UBERON:0013473	88.81	gold quality
apex of heart	UBERON:0002098	88.78	gold quality
sural nerve	UBERON:0015488	88.70	gold quality
bone marrow	UBERON:0002371	88.63	gold quality
spleen	UBERON:0002106	88.62	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.60	gold quality
myometrium	UBERON:0001296	88.41	gold quality
popliteal artery	UBERON:0002250	88.39	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BRCA1, SP1, STAT1, STAT3, TP53

miRNA regulators (miRDB)

43 targeting MDC1, 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-5696	99.98	72.36	4487
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-1284	99.67	73.56	1353
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-185-5P	99.35	68.60	2497

Literature-anchored findings (GeneRIF, showing 40)

• This nuclear protein with signature motifs of FHA and BRCT, and an internal 41-amino acid repeat sequence, is an early participant in DNA damage response. (PMID:12475977)
• role in DNA damage signaling pathways (PMID:12499369)
• NFBD1 is parallel to 53BP1 in regulating Chk2 and downstream of H2AX in the recruitment of repair and signaling proteins to sites of DNA damage in tumor cells (PMID:12551934)
• MDC1-mediated focus formation by the MRE11 complex at sites of DNA damage is crucial for the efficient activation of the intra-S-phase checkpoint (PMID:12607003)
• MDC1 is recruited through its FHA domain to the activated CHK2 and has a critical role in CHK2-mediated DNA damage responses (PMID:12607004)
• role for MDC1 in mediating transduction of the DNA damage signal (PMID:12607005)
• MDC1 regulates BRCA1 function in DNA damage checkpoint control (PMID:12611903)
• NFBD1 has a role in DNA checkpoint signaling and recruits repair proteins to the sites of DNA damage. (PMID:14519663)
• In cells with wild-type Nbs1, suppression of 53BP1 expression had no effect on ATM activation but was associated with increased recruitment of NFBD1/MDC1 and Nbs1 to sites of DNA breaks. (PMID:14695167)
• MDC1 functions as an H2AFX-dependent interaction platform enabling a switch from transient, MDC1-independent interactions with the surrounding chromosomal environment. (PMID:15201865)
• MDC1/NFBD1 appears to be a key regulator of the DNA damage response in mammalian cells [review] (PMID:15279781)
• MDC1 acts not only as a mediator of DNA damage checkpoint but also as a mediator of DNA damage repair (PMID:15377652)
• Both 53BP1 and NFBD1 are required for recruitment of ATR to DNA damage sites, as well as for ATR-dependent phosphorylation in response to DNA damage. (PMID:15734998)
• NFBD1Mdc1/NFBD1 as a key upstream determinant of 53BP1’s interaction with DSBs. (PMID:16009723)
• structural analysis of the BRCT repeat domain of MDC1 and its specificity for the free COOH-terminal end of the gamma-H2AX histone tail (PMID:16049003)
• MDC1 functions in Rad51-mediated homologous recombination by retaining Rad51 in chromatin. (PMID:16186822)
• MDC1 knockdown affected the formation of telomere dysfunction-induced foci. (PMID:17158742)
• NFBD1 plays an important role in the decision of cell survival and death after DNA damage through the regulation of p53 (PMID:17535811)
• Contrary to carcinomas, almost no activation or loss of MDC1 or 53BP1 were found among testicular germ-cell tumours (TGCTs), a tumour type with unique biology and exceptionally low incidence of p53 mutations. (PMID:17546051)
• The results reveal a link between the cellular response to DNA damage and cell cycle regulation, suggesting that MDC1, known to have a role in checkpoint regulation, executes part of this role by binding the APC/C. (PMID:17827148)
• MDC1 and 53BP1 expressions were observed for the first time in human esophageal carcinoma cell lines TE-1,TE-13 and Eca109 cells, at both the mRNA and protein levels. (PMID:17884766)
• MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage (PMID:17925396)
• We found six differentially expressed proteins; among them, the checkpoint mediator protein MDC1 whose expression was disrupted in FANCC-/- cells. (PMID:17977515)
• MDC1-mediated and RNF8-executed histone ubiquitylation protects genome integrity by licensing the DSB-flanking chromatin to concentrate repair factors near the DNA lesions. (PMID:18001824)
• Phospho-dependent FHA domain-mediated binding of RNF8 to MDC1. (PMID:18001825)
• Sp1-mediated transcriptional regulation of NFBD1 plays an important role in the regulation of DNA damage response. (PMID:18173747)
• Ser-Asp-Thr repeats in the MDC1 N terminus recruit NBS1 and increase the local concentration of NBS1 at the sites of chromosomal breakage. (PMID:18411307)
• NFBD1 directly interacts with MDM2 and increases its stability. (PMID:18471438)
• Structure-based single point mutations in Nbs1 were evaluated in vivo and revealed that BRCT2 is essential for an MDC1-dependent relocalization of Nbs1 to DNA damage sites. (PMID:18582474)
• MDC1 is phosphorylated on a cluster of conserved repeat motifs by casein kinase 2 and this phosphorylation promotes direct, phosphorylation-dependent interactions with NBS1. (PMID:18583988)
• MDC1 and BRIT1 may function as tumor-suppressor genes, at least in part by orchestrating proper centrosome duplication and mitotic spindle assembly. (PMID:18635967)
• Nbs1 has a function in ATR signalling in a manner distinct to any role at stalled replication forks. Replication-independent ATR signalling also requires the mediator proteins, 53BP1 and MDC1, providing direct evidence for their role in ATR signalling. (PMID:18664457)
• MDC1 regulates intra-S-phase checkpoint by targeting NBS1 to DNA double-strand breaks (PMID:18678890)
• supports a novel mechanism for the disassembly of MDC1 foci via ubiquitin-proteasome dependent degradation, which appears to be a key step for the efficient assembly of BRCA1 foci (PMID:18757370)
• the interaction between 53BP1 and MDC1 plays a role in the regulation of mitosis (PMID:18986980)
• NFBD1, 53BP1 and BRCA1 have both unique and redundant functions in radiation-induced phosphorylation and localization events in the ATM-Chk2 pathway. (PMID:19001859)
• Nucleotide excision repair-induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response. (PMID:19797077)
• hMDC1 functionally regulates the normal metaphase-to-anaphase transition by modulating the Cdc20-dependent activation of the APC/C (PMID:19826003)
• Data show that the ATM signalling mediator proteins MDC1, RNF8, RNF168 and 53BP1 are also required for heterochromatic DSB repair. (PMID:20081839)
• structure & peptide binding specificity of BRCT domains of MDC1 & BRCA1; crystal structures of BRCA1 & MDC1 bound to peptides show differences in the environment of conserved arginines that determine affinity for peptides with -COO(-) vs -CO-NH(2) termini (PMID:20159462)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mdc1	ENSDARG00000086764
mus_musculus	Mdc1	ENSMUSG00000061607
rattus_norvegicus	Mdc1	ENSRNOG00000032813
caenorhabditis_elegans		WBGENE00018975

Paralogs (1): PAXIP1 (ENSG00000157212)

Protein

Protein identifiers

Mediator of DNA damage checkpoint protein 1 — Q14676 (reviewed: Q14676)

Alternative names: Nuclear factor with BRCT domains 1

All UniProt accessions (6): Q14676, A0A1U9XBC1, A2AB05, A2AB06, A2AB07, H0Y6Z8

UniProt curated annotations — full annotation on UniProt →

Function. Histone reader protein required for checkpoint-mediated cell cycle arrest in response to DNA damage within both the S phase and G2/M phases of the cell cycle. Specifically recognizes and binds histone H2AX phosphorylated at ‘Ser-139’, a marker of DNA damage, serving as a scaffold for the recruitment of DNA repair and signal transduction proteins to discrete foci of DNA damage sites. Also required for downstream events subsequent to the recruitment of these proteins. These include phosphorylation and activation of the ATM, CHEK1 and CHEK2 kinases, and stabilization of TP53/p53 and apoptosis. ATM and CHEK2 may also be activated independently by a parallel pathway mediated by TP53BP1. Required for chromosomal stability during mitosis by promoting recruitment of TOPBP1 to DNA double strand breaks (DSBs): TOPBP1 forms filamentous assemblies that bridge MDC1 and tether broken chromosomes during mitosis. Required for the repair of DSBs via homologous recombination by promoting recruitment of NBN component of the MRN complex to DSBs.

Subunit / interactions. Homodimer. Interacts with H2AX, which requires phosphorylation of H2AX on ‘Ser-139’. Interacts with the MRN complex, composed of MRE11, RAD50, and NBN. Interacts with CHEK2, which requires ATM-mediated phosphorylation of ‘Thr-68’ within the FHA domain of CHEK2. Interacts constitutively with the BRCA1-BARD1 complex, SMC1A and TP53BP1. Interacts with ATM and FANCD2, and these interactions are reduced upon DNA damage. Also interacts with the PRKDC complex, composed of XRCC6/KU70, XRCC5/KU80 and PRKDC/XRCC7. This interaction may be required for PRKDC autophosphorylation, which is essential for DNA double strand break (DSB) repair. When phosphorylated by ATM, interacts with RNF8 (via FHA domain). Interacts with CEP164. When phosphorylated, interacts with APTX (via FHA-like domain). Interacts (when phosphorylated) with TOPBP1; promoting TOPBP1 localization to DNA damage sites during mitosis. Interacts (when phosphorylated) with NBN; promoting NBN and MRN complex localization to DNA damage sites.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Highly expressed in testis.

Post-translational modifications. Phosphorylated upon exposure to ionizing radiation (IR), ultraviolet radiation (UV), and hydroxyurea (HU). Phosphorylation in response to IR requires ATM, NBN, and possibly CHEK2. Also phosphorylated during the G2/M phase of the cell cycle and during activation of the mitotic spindle checkpoint. Phosphorylation at Thr-4 by ATM stabilizes and enhances homodimerization via the FHA domain. Phosphorylated at Ser-168 and Ser-196 by CK2 in response to DNA damage during mitosis, promoting interaction with TOPBP1. Phosphorylated by CK2 in response to DNA damage, promoting interaction with NBN and recruitment of the MRN complex to DNA damage sites. Sumoylation at Lys-1840 by PIAS4 following DNA damage promotes ubiquitin-mediated degradation. Ubiquitinated by RNF4, leading to proteasomal degradation; undergoes ‘Lys-48’-linked polyubiquitination. Methylated at Lys-45. Demethylation at Lys-45 by JMJD1C after exposure to IR promotes MDC1-RNF8 interaction, RNF8-dependent MDC1 ubiquitination and recruitment of RAP80-BRCA1 to polyubiquitylated MDC1.

Domain organisation. Tandemly repeated BRCT domains are characteristic of proteins involved in DNA damage signaling. In MDC1, these repeats are required for localization to chromatin which flanks sites of DNA damage marked by ‘Ser-139’ phosphorylation of H2AX.

Isoforms (4)

UniProt ID	Names	Canonical?
Q14676-1	1	yes
Q14676-2	2
Q14676-3	3
Q14676-4	4

RefSeq proteins (1): NP_055456* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000253	FHA_dom	Domain
IPR001357	BRCT_dom	Domain
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR036420	BRCT_dom_sf	Homologous_superfamily
IPR051579	DDR_Transcriptional_Reg	Family

Pfam: PF00498, PF16589, PF16770

UniProt features (203 total): modified residue 75, compositionally biased region 30, sequence variant 19, strand 15, region of interest 12, helix 12, mutagenesis site 11, sequence conflict 11, cross-link 8, domain 3, splice variant 3, turn 3, chain 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
2ETX	X-RAY DIFFRACTION	1.33
3K05	X-RAY DIFFRACTION	1.33
2ADO	X-RAY DIFFRACTION	1.45
3UMZ	X-RAY DIFFRACTION	1.65
3UNN	X-RAY DIFFRACTION	1.7
3UNM	X-RAY DIFFRACTION	1.8
3UOT	X-RAY DIFFRACTION	1.8
3UN0	X-RAY DIFFRACTION	2.3
9QJZ	X-RAY DIFFRACTION	2.31
2AZM	X-RAY DIFFRACTION	2.41
9IF9	X-RAY DIFFRACTION	2.55
3UEO	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14676-F1	40.39	0.13

Functional residue map

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

Post-translational modifications (83): 1425, 1466, 1548, 1564, 1567, 1589, 1604, 1608, 1630, 1664, 1671, 1681, 1697, 1702, 1711, 1740, 1775, 1800, 1820, 1858 …

Mutagenesis-validated functional residues (11):

Position	Phenotype
45	constitutively enhanced interaction with rnf8.
58	abrogates binding to the mre11 complex and to chek2.
72	abrogates binding to chek2.
96	abrogates binding to chek2; when associated with a-97 and a-98.
97	abrogates binding to chek2; when associated with a-96 and a-98.
98	abrogates binding to chek2; when associated with a-96 and a-97.
168	decreased phosphorylation by ck2, leading to impaired interaction with topbp1; when associated with a-196.
196	decreased phosphorylation by ck2, leading to impaired interaction with topbp1; when associated with a-168.
299–301	decreased phosphorylation by ck2, leading to impaired interaction with nbn.
453–455	decreased phosphorylation by ck2, leading to impaired interaction with nbn.
1840	suppresses rnf4-mediated ubiquitination, accumulates at sites of dna damage, defective homologous recombination.

Function

Pathways and Gene Ontology

Reactome pathways

22 pathways

ID	Pathway
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-1640170	Cell Cycle
R-HSA-212436	Generic Transcription Pathway
R-HSA-2990846	SUMOylation
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-392499	Metabolism of proteins
R-HSA-5693532	DNA Double-Strand Break Repair
R-HSA-5693538	Homology Directed Repair
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)
R-HSA-5693606	DNA Double Strand Break Response
R-HSA-597592	Post-translational protein modification
R-HSA-69481	G2/M Checkpoints
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-73894	DNA Repair
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 234 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, BROWNE_HCMV_INFECTION_6HR_DN, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MITOTIC_INTRA_S_DNA_DAMAGE_CHECKPOINT_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_NEGATIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GOBP_DNA_DAMAGE_RESPONSE, GOBP_MITOTIC_DNA_INTEGRITY_CHECKPOINT_SIGNALING, GOBP_MITOTIC_CELL_CYCLE, GOBP_DNA_REPLICATION_CHECKPOINT_SIGNALING

GO Biological Process (8): DNA replication checkpoint signaling (GO:0000076), DNA repair (GO:0006281), DNA damage response (GO:0006974), mitotic intra-S DNA damage checkpoint signaling (GO:0031573), protein localization to site of double-strand break (GO:1990166), chromatin organization (GO:0006325), protein K6-linked ubiquitination (GO:0085020), positive regulation of double-strand break repair via homologous recombination (GO:1905168)

GO Molecular Function (3): chromatin-protein adaptor activity (GO:0140463), histone reader activity (GO:0140566), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), focal adhesion (GO:0005925), nuclear body (GO:0016604), site of double-strand break (GO:0035861)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
DNA Double-Strand Break Repair	3
SUMO E3 ligases SUMOylate target proteins	1
DNA Double Strand Break Response	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
Transcriptional Regulation by TP53	1
G2/M Checkpoints	1
RNA Polymerase II Transcription	1
Post-translational protein modification	1
SUMOylation	1
Generic Transcription Pathway	1
DNA Repair	1
Homology Directed Repair	1
Metabolism of proteins	1
Cell Cycle Checkpoints	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membraneless organelle	2
DNA integrity checkpoint signaling	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
mitotic S phase	1
mitotic DNA damage checkpoint signaling	1
protein localization to chromosome	1
cellular component organization	1
protein polyubiquitination	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
positive regulation of DNA recombination	1
positive regulation of double-strand break repair	1
chromatin binding	1
chromatin organization	1
protein-macromolecule adaptor activity	1
nucleosome	1
histone binding	1
chromatin-protein adaptor activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
cell-substrate junction	1
nucleoplasm	1
site of DNA damage	1

Protein interactions and networks

STRING

2760 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MDC1	RNF8	O76064	999
MDC1	TP53BP1	Q12888	999
MDC1	H2AX	P16104	998
MDC1	ATM	Q13315	997
MDC1	BRCA1	P38398	996
MDC1	RNF168	Q8IYW5	995
MDC1	UIMC1	Q96RL1	978
MDC1	CHEK2	O96017	965
MDC1	SMC3	Q9UQE7	961
MDC1	TOPBP1	Q92547	950
MDC1	RBBP8	Q99708	917
MDC1	RAD9A	Q99638	898
MDC1	CHEK1	O14757	896
MDC1	XRCC6	P12956	889
MDC1	RAD51	Q06609	886

IntAct

191 interactions, top by confidence:

A	B	Type	Score
NBN	MDC1	psi-mi:“MI:0915”(physical association)	0.970
NBN	MDC1	psi-mi:“MI:0403”(colocalization)	0.970
MDC1	H2AX	psi-mi:“MI:0403”(colocalization)	0.970
MDC1	NBN	psi-mi:“MI:0915”(physical association)	0.970
H2AX	MDC1	psi-mi:“MI:0915”(physical association)	0.970
MDC1	H2AX	psi-mi:“MI:0407”(direct interaction)	0.970
NBN	MDC1	psi-mi:“MI:0407”(direct interaction)	0.970
MDC1	NBN	psi-mi:“MI:0407”(direct interaction)	0.970
MDC1	NBN	psi-mi:“MI:0914”(association)	0.970
MDC1	H2AX	psi-mi:“MI:0915”(physical association)	0.970

BioGRID (682): MDC1 (Affinity Capture-MS), MDC1 (Affinity Capture-MS), MDC1 (Affinity Capture-MS), MDC1 (Reconstituted Complex), MDC1 (Affinity Capture-Western), MDC1 (Affinity Capture-Western), RNF8 (Affinity Capture-Western), HNRNPU (Co-fractionation), MDC1 (Co-fractionation), MDC1 (Co-fractionation), MDC1 (Co-fractionation), SMARCC1 (Co-fractionation), SMARCD2 (Co-fractionation), SSBP3 (Co-fractionation), MDC1 (Biochemical Activity)

ESM2 similar proteins: A2ADZ8, A6NNH2, D2J0Y4, D3YU32, P0C2Y1, Q0VET5, Q12802, Q14676, Q149B8, Q283Q6, Q2TBI7, Q3KR64, Q3U0P1, Q4KMZ1, Q4R736, Q5QJ38, Q5R5G4, Q5T1N1, Q5TM68, Q5VWK0, Q5VYM1, Q5ZK13, Q68A65, Q6AZ54, Q6NXZ1, Q6PG16, Q6PIX9, Q7YR40, Q7Z572, Q86Y26, Q8BHP2, Q8BHW6, Q8C0D9, Q8C5V8, Q8C9M2, Q8CGM2, Q8N5Q1, Q8NCD3, Q8WP21, Q924C5

Diamond homologs: A0JNA8, Q14676, Q5PSV9, Q5TM68, Q5U2M8, Q5XIY8, Q6NZQ4, Q6ZQF0, Q6ZW49, Q767L8, Q7YR40, Q7ZZY3, Q800K6, Q90WJ3, Q92547, Q10337

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
H2AX	up-regulates	MDC1	binding
BAZ1B	down-regulates	MDC1
MDC1	up-regulates	RNF8	relocalization
CSNK2A1	up-regulates	MDC1	phosphorylation
MDC1	up-regulates	NBN	binding
L3MBTL2	“up-regulates activity”	MDC1	binding
ASF1A	“up-regulates activity”	MDC1	binding
ATM	up-regulates	MDC1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 155 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
DNA Double Strand Break Response	6	26.4×	1e-05
Impaired BRCA2 binding to PALB2	5	21.1×	2e-04
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	5	19.6×	2e-04
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	5	19.6×	2e-04
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	5	19.6×	2e-04
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	5	18.2×	3e-04
Homologous DNA Pairing and Strand Exchange	5	17.6×	3e-04
Nonhomologous End-Joining (NHEJ)	10	15.6×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of telomere maintenance	5	18.5×	2e-03
double-strand break repair	11	16.2×	9e-08
mitotic G2 DNA damage checkpoint signaling	5	16.1×	2e-03
positive regulation of DNA repair	6	15.6×	7e-04
double-strand break repair via nonhomologous end joining	5	15.3×	2e-03
response to ionizing radiation	5	14.9×	2e-03
double-strand break repair via homologous recombination	10	11.3×	1e-05
telomere maintenance	5	9.7×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	201
Likely benign	40
Benign	15

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3901150	NM_014641.3(MDC1):c.5644C>T (p.Arg1882Ter)	Pathogenic
3901151	NM_014641.3(MDC1):c.1A>T (p.Met1Leu)	Pathogenic
3901223	NM_014641.3(MDC1):c.5977C>T (p.Arg1993Ter)	Pathogenic

SpliceAI

2297 predictions. Top by Δscore:

Variant	Effect	Δscore
6:30702547:GCATA:G	donor_loss	1.0000
6:30702548:CATAC:C	donor_loss	1.0000
6:30702549:ATAC:A	donor_loss	1.0000
6:30702550:TACC:T	donor_loss	1.0000
6:30702551:A:T	donor_loss	1.0000
6:30702662:CC:C	acceptor_gain	1.0000
6:30702663:CC:C	acceptor_gain	1.0000
6:30702663:CCTAA:C	acceptor_loss	1.0000
6:30702664:CTAAG:C	acceptor_loss	1.0000
6:30702665:T:C	acceptor_loss	1.0000
6:30702746:TCTCA:T	donor_loss	1.0000
6:30702747:CTCA:C	donor_loss	1.0000
6:30702748:TCA:T	donor_loss	1.0000
6:30702749:CACCT:C	donor_loss	1.0000
6:30702750:A:C	donor_loss	1.0000
6:30702751:CCT:C	donor_gain	1.0000
6:30702848:C:T	acceptor_gain	1.0000
6:30702878:C:CC	acceptor_gain	1.0000
6:30703413:CTTA:C	donor_loss	1.0000
6:30703414:TTAC:T	donor_loss	1.0000
6:30703415:TACTT:T	donor_loss	1.0000
6:30703416:A:AC	donor_gain	1.0000
6:30703417:C:CC	donor_gain	1.0000
6:30703534:CATC:C	acceptor_gain	1.0000
6:30703537:CCT:C	acceptor_loss	1.0000
6:30703538:C:CC	acceptor_gain	1.0000
6:30703538:CTGAG:C	acceptor_loss	1.0000
6:30703539:T:C	acceptor_loss	1.0000
6:30707382:AC:A	donor_gain	1.0000
6:30707383:CC:C	donor_gain	1.0000

AlphaMissense

13497 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:30703115:A:G	W1952R	0.997
6:30703115:A:T	W1952R	0.997
6:30703279:A:G	F1897S	0.997
6:30703278:G:C	F1897L	0.996
6:30703278:G:T	F1897L	0.996
6:30703280:A:G	F1897L	0.996
6:30702800:A:C	F1981L	0.994
6:30702800:A:T	F1981L	0.994
6:30702802:A:G	F1981L	0.994
6:30703113:C:A	W1952C	0.994
6:30703113:C:G	W1952C	0.994
6:30703159:A:G	F1937S	0.994
6:30700538:A:G	L2066P	0.993
6:30703156:A:G	L1938P	0.993
6:30703158:G:C	F1937L	0.993
6:30703158:G:T	F1937L	0.993
6:30703160:A:G	F1937L	0.993
6:30700543:G:C	F2064L	0.992
6:30700543:G:T	F2064L	0.992
6:30700545:A:G	F2064L	0.992
6:30703165:A:T	V1935D	0.992
6:30703189:A:T	V1927D	0.992
6:30714094:C:G	A76P	0.992
6:30703129:A:T	I1947N	0.991
6:30700544:A:G	F2064S	0.990
6:30700616:A:T	I2040N	0.990
6:30714038:G:C	S94R	0.990
6:30714038:G:T	S94R	0.990
6:30714040:T:G	S94R	0.990
6:30700498:A:C	F2079L	0.989

dbSNP variants (sampled 300 via entrez): RS1000262648 (6:30704777 G>C), RS1000265611 (6:30704572 G>A,T), RS1000280636 (6:30716116 T>C), RS1000734021 (6:30716348 C>T), RS1000854870 (6:30710678 T>C), RS1001013815 (6:30717500 G>A,C), RS1001089492 (6:30710346 C>T), RS1001121983 (6:30710080 T>C), RS1001499935 (6:30699341 C>T), RS1001737685 (6:30715649 CTTT>C,CTT), RS1001827918 (6:30699577 T>C), RS1002038200 (6:30719141 A>G), RS1002069878 (6:30717166 C>A), RS1002129942 (6:30711360 A>G), RS1002275512 (6:30709983 A>G)

Disease associations

OMIM: gene MIM:607593 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): oligoasthenoteratozoospermia (MONDO:0850098)

Orphanet (0):

HPO phenotypes

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

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_121	Autism spectrum disorder or schizophrenia	3.000000e-13
GCST004521_132	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004521_171	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_2	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_210	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_263	Autism spectrum disorder or schizophrenia	7.000000e-17
GCST004521_265	Autism spectrum disorder or schizophrenia	7.000000e-14
GCST004521_295	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_3	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_48	Autism spectrum disorder or schizophrenia	1.000000e-09
GCST004521_56	Autism spectrum disorder or schizophrenia	1.000000e-22
GCST004521_70	Autism spectrum disorder or schizophrenia	8.000000e-20
GCST004521_79	Autism spectrum disorder or schizophrenia	1.000000e-16
GCST009456_9	Eosinophil count	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725194 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

Binding affinities (BindingDB)

5 measured of 7 human assays (7 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CC-220 (Compound 6)	IC50	28 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
3-(4-((4-(morpholinomethyl)benzyl)-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione	IC50	190 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
19171-19-8	IC50	230 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione	IC50	300 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
(R)-3-(4-((4-(morpholinomethyl)benzyl)-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione	IC50	450 nM	US-9694015: Methods for the treatment of locally advanced breast cancer

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.89	IC50	1300	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178780: Inhibition of MDC1 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	1.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	decreases expression, decreases phosphorylation, affects expression, affects response to substance	3
Benzo(a)pyrene	increases expression	2
Cisplatin	decreases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
urushiol	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	increases expression	1
trichostatin A	affects expression	1
riddelliine	decreases expression, increases metabolic processing	1
arsenite	affects binding, decreases reaction	1
tetrabromobisphenol A	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
coumarin	affects phosphorylation	1
casticin	increases expression	1
CPG-oligonucleotide	decreases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
Bortezomib	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Troglitazone	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697510	Binding	Inhibition of MDC1 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

8 cell lines: 8 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1Q96	H414-MDC1(+/-)	Cancer cell line	Male
CVCL_1Q97	H414-MDC1(-/-)	Cancer cell line	Male
CVCL_1R05	HCT116-MDC1(+/-)	Cancer cell line	Male
CVCL_1R06	HCT116-MDC1(-/-)	Cancer cell line	Male
CVCL_B8K7	Abcam HCT 116 MDC1 KO	Cancer cell line	Male
CVCL_B8YP	Abcam MCF-7 MDC1 KO	Cancer cell line	Female
CVCL_B9MG	Abcam A-549 MDC1 KO	Cancer cell line	Male
CVCL_SX66	HAP1 MDC1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07579858	PHASE3	COMPLETED	PRP Improves Blastocyst Formation in ICSI Cycles
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT02752555	Not specified	UNKNOWN	Severe Male Factor Infertility Management
NCT06088693	Not specified	COMPLETED	The Role of Electroacupuncture With Standard Therapy on Sperm Analysis and SOD Levels in Oligozoospermia.
NCT07286279	Not specified	COMPLETED	Identifying Candidates for Limited Dissection at Microdissection TESE.
NCT07345455	Not specified	RECRUITING	Probiotics on Sperm Quality in Male Infertility Patients