Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT40DNXU)

• DOT Name: DNA ligase 4 (LIG4)
• Synonyms: EC 6.5.1.1; DNA ligase IV; Polydeoxyribonucleotide synthase 4
• Gene Name: LIG4
• Related Disease:
  DNA ligase IV deficiency
  Glioma
  Isolated growth hormone deficiency type IA
  Non-insulin dependent diabetes
  Thrombocytopenia
  Type-1/2 diabetes
  Acute lymphocytic leukaemia
  Adult glioblastoma
  Ataxia-telangiectasia
  B-cell lymphoma
  B-cell neoplasm
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Hepatocellular carcinoma
  Isolated congenital microcephaly
  leukaemia
  Lymphoma
  Malignant glioma
  Melanoma
  Myeloproliferative neoplasm
  Neoplasm
  Nijmegen breakage syndrome
  Non-small-cell lung cancer
  Pancreatic cancer
  Pancytopenia
  Rheumatoid arthritis
  Schizophrenia
  Seckel syndrome
  Severe combined immunodeficiency
  Severe combined immunodeficiency due to DCLRE1C deficiency
  Small lymphocytic lymphoma
  Stomach cancer
  Xeroderma pigmentosum
  Amyotrophic lateral sclerosis
  Leukemia
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Dubowitz syndrome
  Omenn syndrome
  Chromosomal disorder
  Epithelial ovarian cancer
  Hepatitis C virus infection
  Myelodysplastic syndrome
  Neuroblastoma
  Ovarian cancer
  Ovarian neoplasm
  Squamous cell carcinoma
• UniProt ID: DNLI4_HUMAN
• PDB ID: 1IK9; 2E2W; 3II6; 3VNN; 3W1B; 3W1G; 3W5O; 4HTO; 4HTP; 6BKF; 6BKG; 7D9K; 7D9Y; 7LSY; 7LT3; 7NFC; 7NFE; 8BH3; 8BHV; 8BHY; 8BOT; 8EZA; 8EZB
• EC Number: 6.5.1.1
• Pfam ID: PF00533 ; PF04679 ; PF01068 ; PF04675 ; PF11411
• Sequence:
  MAASQTSQTVASHVPFADLCSTLERIQKSKGRAEKIRHFREFLDSWRKFHDALHKNHKDV
  TDSFYPAMRLILPQLERERMAYGIKETMLAKLYIELLNLPRDGKDALKLLNYRTPTGTHG
  DAGDFAMIAYFVLKPRCLQKGSLTIQQVNDLLDSIASNNSAKRKDLIKKSLLQLITQSSA
  LEQKWLIRMIIKDLKLGVSQQTIFSVFHNDAAELHNVTTDLEKVCRQLHDPSVGLSDISI
  TLFSAFKPMLAAIADIEHIEKDMKHQSFYIETKLDGERMQMHKDGDVYKYFSRNGYNYTD
  QFGASPTEGSLTPFIHNAFKADIQICILDGEMMAYNPNTQTFMQKGTKFDIKRMVEDSDL
  QTCYCVFDVLMVNNKKLGHETLRKRYEILSSIFTPIPGRIEIVQKTQAHTKNEVIDALNE
  AIDKREEGIMVKQPLSIYKPDKRGEGWLKIKPEYVSGLMDELDILIVGGYWGKGSRGGMM
  SHFLCAVAEKPPPGEKPSVFHTLSRVGSGCTMKELYDLGLKLAKYWKPFHRKAPPSSILC
  GTEKPEVYIEPCNSVIVQIKAAEIVPSDMYKTGCTLRFPRIEKIRDDKEWHECMTLDDLE
  QLRGKASGKLASKHLYIGGDDEPQEKKRKAAPKMKKVIGIIEHLKAPNLTNVNKISNIFE
  DVEFCVMSGTDSQPKPDLENRIAEFGGYIVQNPGPDTYCVIAGSENIRVKNIILSNKHDV
  VKPAWLLECFKTKSFVPWQPRFMIHMCPSTKEHFAREYDCYGDSYFIDTDLNQLKEVFSG
  IKNSNEQTPEEMASLIADLEYRYSWDCSPLSMFRRHTVYLDSYAVINDLSTKNEGTRLAI
  KALELRFHGAKVVSCLAEGVSHVIIGEDHSRVADFKAFRRTFKRKFKILKESWVTDSIDK
  CELQEENQYLI
• Function: DNA ligase involved in DNA non-homologous end joining (NHEJ); required for double-strand break (DSB) repair and V(D)J recombination. Catalyzes the NHEJ ligation step of the broken DNA during DSB repair by resealing the DNA breaks after the gap filling is completed. Joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. LIG4 is mechanistically flexible: it can ligate nicks as well as compatible DNA overhangs alone, while in the presence of XRCC4, it can ligate ends with 2-nucleotides (nt) microhomology and 1-nt gaps. Forms a subcomplex with XRCC4; the LIG4-XRCC4 subcomplex is responsible for the NHEJ ligation step and XRCC4 enhances the joining activity of LIG4. Binding of the LIG4-XRCC4 complex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends. LIG4 regulates nuclear localization of XRCC4.
• Tissue Specificity: Testis, thymus, prostate and heart.
• KEGG Pathway: Non-homologous end-joining (hsa03450)
• Reactome Pathway:
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  2-LTR circle formation (R-HSA-164843)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
DNA ligase IV deficiency	DIS69O87	Definitive	Autosomal recessive	[1]
Glioma	DIS5RPEH	Definitive	Genetic Variation	[2]
Isolated growth hormone deficiency type IA	DISLPIAM	Definitive	CausalMutation	[3]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[4]
Thrombocytopenia	DISU61YW	Definitive	CausalMutation	[3]
Type-1/2 diabetes	DISIUHAP	Definitive	Genetic Variation	[5]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[6]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[7]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[8]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[9]
B-cell neoplasm	DISVY326	Strong	Genetic Variation	[10]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[11]
Colon cancer	DISVC52G	Strong	Altered Expression	[12]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[12]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[14]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[10]
leukaemia	DISS7D1V	Strong	Altered Expression	[15]
Lymphoma	DISN6V4S	Strong	Biomarker	[6]
Malignant glioma	DISFXKOV	Strong	Altered Expression	[16]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[17]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Genetic Variation	[18]
Neoplasm	DISZKGEW	Strong	Altered Expression	[19]
Nijmegen breakage syndrome	DIS98HVL	Strong	Genetic Variation	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[20]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[21]
Pancytopenia	DISVKEHV	Strong	Biomarker	[22]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[23]
Schizophrenia	DISSRV2N	Strong	Biomarker	[24]
Seckel syndrome	DISEVUBA	Strong	Genetic Variation	[18]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Biomarker	[22]
Severe combined immunodeficiency due to DCLRE1C deficiency	DISR36ZW	Strong	Biomarker	[25]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[26]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[27]
Xeroderma pigmentosum	DISQ9H19	Strong	Biomarker	[28]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[29]
Leukemia	DISNAKFL	moderate	Altered Expression	[15]
Plasma cell myeloma	DIS0DFZ0	moderate	Genetic Variation	[30]
Prostate cancer	DISF190Y	moderate	Altered Expression	[31]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[31]
Dubowitz syndrome	DISRMNLQ	Supportive	Autosomal recessive	[32]
Omenn syndrome	DIS2C887	Supportive	Autosomal recessive	[33]
Chromosomal disorder	DISM5BB5	Limited	Biomarker	[34]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[35]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[36]
Myelodysplastic syndrome	DISYHNUI	Limited	Biomarker	[37]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[38]
Ovarian cancer	DISZJHAP	Limited	Genetic Variation	[35]
Ovarian neoplasm	DISEAFTY	Limited	Genetic Variation	[35]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[39]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DNA ligase 4 (LIG4).	[40]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA ligase 4 (LIG4).	[41]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA ligase 4 (LIG4).	[42]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of DNA ligase 4 (LIG4).	[43]
Marinol	DM70IK5	Approved	Marinol increases the expression of DNA ligase 4 (LIG4).	[44]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of DNA ligase 4 (LIG4).	[45]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of DNA ligase 4 (LIG4).	[46]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of DNA ligase 4 (LIG4).	[47]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA ligase 4 (LIG4).	[48]
Fenfluramine	DM0762O	Phase 3	Fenfluramine increases the expression of DNA ligase 4 (LIG4).	[49]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of DNA ligase 4 (LIG4).	[51]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of DNA ligase 4 (LIG4).	[52]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of DNA ligase 4 (LIG4).	[53]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of DNA ligase 4 (LIG4).	[54]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of DNA ligase 4 (LIG4).	[50]

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