Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEUQH4J)

• DOT Name: Mediator of DNA damage checkpoint protein 1 (MDC1)
• Synonyms: Nuclear factor with BRCT domains 1
• Gene Name: MDC1
• Related Disease:
  Advanced cancer
  Ataxia-telangiectasia
  Bladder cancer
  Carcinoma
  Carcinoma of esophagus
  Carotid stenosis
  Cervical cancer
  Cervical carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Esophageal cancer
  Gastric cancer
  Glioma
  Malignant tumor of nasopharynx
  Metastatic malignant neoplasm
  Mismatch repair cancer syndrome
  Nasopharyngeal carcinoma
  Neoplasm of esophagus
  Ovarian cancer
  Ovarian neoplasm
  Rheumatoid arthritis
  Squamous cell carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  X-linked congenital generalized hypertrichosis
  Breast cancer
  Breast carcinoma
  Laryngeal squamous cell carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Matthew-Wood syndrome
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
• UniProt ID: MDC1_HUMAN
• PDB ID: 2ADO; 2AZM; 2ETX; 3K05; 3UEO; 3UMZ; 3UN0; 3UNM; 3UNN; 3UOT
• Pfam ID: PF16589 ; PF00498 ; PF16770
• Sequence:
  MEDTQAIDWDVEEEEETEQSSESLRCNVEPVGRLHIFSGAHGPEKDFPLHLGKNVVGRMP
  DCSVALPFPSISKQHAEIEILAWDKAPILRDCGSLNGTQILRPPKVLSPGVSHRLRDQEL
  ILFADLLCQYHRLDVSLPFVSRGPLTVEETPRVQGETQPQRLLLAEDSEEEVDFLSERRM
  VKKSRTTSSSVIVPESDEEGHSPVLGGLGPPFAFNLNSDTDVEEGQQPATEEASSAARRG
  ATVEAKQSEAEVVTEIQLEKDQPLVKERDNDTKVKRGAGNGVVPAGVILERSQPPGEDSD
  TDVDDDSRPPGRPAEVHLERAQPFGFIDSDTDAEEERIPATPVVIPMKKRKIFHGVGTRG
  PGAPGLAHLQESQAGSDTDVEEGKAPQAVPLEKSQASMVINSDTDDEEEVSAALTLAHLK
  ESQPAIWNRDAEEDMPQRVVLLQRSQTTTERDSDTDVEEEELPVENREAVLKDHTKIRAL
  VRAHSEKDQPPFGDSDDSVEADKSSPGIHLERSQASTTVDINTQVEKEVPPGSAIIHIKK
  HQVSVEGTNQTDVKAVGGPAKLLVVSLEEAWPLHGDCETDAEEGTSLTASVVADVRKSQL
  PAEGDAGAEWAAAVLKQERAHEVGAQGGPPVAQVEQDLPISRENLTDLVVDTDTLGESTQ
  PQREGAQVPTGREREQHVGGTKDSEDNYGDSEDLDLQATQCFLENQGLEAVQSMEDEPTQ
  AFMLTPPQELGPSHCSFQTTGTLDEPWEVLATQPFCLRESEDSETQPFDTHLEAYGPCLS
  PPRAIPGDQHPESPVHTEPMGIQGRGRQTVDKVMGIPKETAERVGPERGPLERETEKLLP
  ERQTDVTGEEELTKGKQDREQKQLLARDTQRQESDKNGESASPERDRESLKVEIETSEEI
  QEKQVQKQTLPSKAFEREVERPVANRECDPAELEEKVPKVILERDTQRGEPEGGSQDQKG
  QASSPTPEPGVGAGDLPGPTSAPVPSGSQSGGRGSPVSPRRHQKGLLNCKMPPAEKASRI
  RAAEKVSRGDQESPDACLPPTVPEAPAPPQKPLNSQSQKHLAPPPLLSPLLPSIKPTVRK
  TRQDGSQEAPEAPLSSELEPFHPKPKIRTRKSSRMTPFPATSAAPEPHPSTSTAQPVTPK
  PTSQATRSRTNRSSVKTPEPVVPTAPELQPSTSTDQPVTSEPTSQVTRGRKSRSSVKTPE
  TVVPTALELQPSTSTDRPVTSEPTSQATRGRKNRSSVKTPEPVVPTAPELQPSTSTDQPV
  TSEPTYQATRGRKNRSSVKTPEPVVPTAPELRPSTSTDRPVTPKPTSRTTRSRTNMSSVK
  TPETVVPTAPELQISTSTDQPVTPKPTSRTTRSRTNMSSVKNPESTVPIAPELPPSTSTE
  QPVTPEPTSRATRGRKNRSSGKTPETLVPTAPKLEPSTSTDQPVTPEPTSQATRGRTNRS
  SVKTPETVVPTAPELQPSTSTDQPVTPEPTSQATRGRTDRSSVKTPETVVPTAPELQASA
  STDQPVTSEPTSRTTRGRKNRSSVKTPETVVPAAPELQPSTSTDQPVTPEPTSRATRGRT
  NRSSVKTPESIVPIAPELQPSTSRNQLVTPEPTSRATRCRTNRSSVKTPEPVVPTAPEPH
  PTTSTDQPVTPKLTSRATRRKTNRSSVKTPKPVEPAASDLEPFTPTDQSVTPEAIAQGGQ
  SKTLRSSTVRAMPVPTTPEFQSPVTTDQPISPEPITQPSCIKRQRAAGNPGSLAAPIDHK
  PCSAPLEPKSQASRNQRWGAVRAAESLTAIPEPASPQLLETPIHASQIQKVEPAGRSRFT
  PELQPKASQSRKRSLATMDSPPHQKQPQRGEVSQKTVIIKEEEEDTAEKPGKEEDVVTPK
  PGKRKRDQAEEEPNRIPSRSLRRTKLNQESTAPKVLFTGVVDARGERAVLALGGSLAGSA
  AEASHLVTDRIRRTVKFLCALGRGIPILSLDWLHQSRKAGFFLPPDEYVVTDPEQEKNFG
  FSLQDALSRARERRLLEGYEIYVTPGVQPPPPQMGEIISCCGGTYLPSMPRSYKPQRVVI
  TCPQDFPHCSIPLRVGLPLLSPEFLLTGVLKQEAKPEAFVLSPLEMSST
• 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.
• Tissue Specificity: Highly expressed in testis.
• Reactome Pathway:
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  G2/M DNA damage checkpoint (R-HSA-69473)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Ataxia-telangiectasia	DISP3EVR	Strong	Altered Expression	[2]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[5]
Carotid stenosis	DISZA8D0	Strong	Altered Expression	[6]
Cervical cancer	DISFSHPF	Strong	Biomarker	[7]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[7]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[8]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[10]
Gastric cancer	DISXGOUK	Strong	Biomarker	[11]
Glioma	DIS5RPEH	Strong	Biomarker	[12]
Malignant tumor of nasopharynx	DISTGIGF	Strong	Biomarker	[13]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[9]
Mismatch repair cancer syndrome	DISIXHJ2	Strong	Altered Expression	[8]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[14]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[10]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[15]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[16]
Stomach cancer	DISKIJSX	Strong	Biomarker	[11]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[3]
X-linked congenital generalized hypertrichosis	DISVL46B	Strong	Biomarker	[17]
Breast cancer	DIS7DPX1	moderate	Biomarker	[18]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[18]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Biomarker	[19]
Lung cancer	DISCM4YA	moderate	Genetic Variation	[1]
Lung carcinoma	DISTR26C	moderate	Genetic Variation	[1]
Neoplasm	DISZKGEW	Disputed	Biomarker	[20]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[20]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[20]
Prostate cancer	DISF190Y	Limited	Biomarker	[21]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[21]

20 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[22]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[27]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[30]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[31]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[31]
Marinol	DM70IK5	Approved	Marinol increases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[32]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[33]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[34]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[35]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[36]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[38]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[41]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[42]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Mediator of DNA damage checkpoint protein 1 (MDC1).	[43]

6 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mediator of DNA damage checkpoint protein 1 (MDC1).	[28]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Mediator of DNA damage checkpoint protein 1 (MDC1).	[29]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Mediator of DNA damage checkpoint protein 1 (MDC1).	[39]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Mediator of DNA damage checkpoint protein 1 (MDC1).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Mediator of DNA damage checkpoint protein 1 (MDC1).	[29]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Mediator of DNA damage checkpoint protein 1 (MDC1).	[44]

References

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