Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT895FEC)

• DOT Name: Germinal-center associated nuclear protein (MCM3AP)
• Synonyms: GANP; EC 2.3.1.48; 80 kDa MCM3-associated protein; MCM3 acetylating protein; MCM3AP; EC 2.3.1.-; MCM3 acetyltransferase
• Gene Name: MCM3AP
• Related Disease:
  Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development
  Advanced cancer
  Breast neoplasm
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 4J
  Cholangiocarcinoma
  Congenital contractural arachnodactyly
  High blood pressure
  Immunodeficiency
  Intellectual disability
  Malignant glioma
  Myelodysplastic syndrome
  Neoplasm
  Neoplasm of testis
  Testicular germ cell tumor
  Breast cancer
  Breast carcinoma
  Familial periodic paralysis
  Periodontitis
  Hepatocellular carcinoma
  Classic Hodgkin lymphoma
  Lymphoma
  Melanocytic nevus
• UniProt ID: GANP_HUMAN
• PDB ID: 4DHX
• EC Number: 2.3.1.-; 2.3.1.48
• Pfam ID: PF16766 ; PF16769 ; PF16768 ; PF03399
• Sequence:
  MNPTNPFSGQQPSAFSASSSNVGTLPSKPPFRFGQPSLFGQNSTLSGKSSGFSQVSSFPA
  SSGVSHSSSVQTLGFTQTSSVGPFSGLEHTSTFVATSGPSSSSVLGNTGFSFKSPTSVGA
  FPSTSAFGQEAGEIVNSGFGKTEFSFKPLENAVFKPILGAESEPEKTQSQIASGFFTFSH
  PISSAPGGLAPFSFPQVTSSSATTSNFTFSKPVSSNNSLSAFTPALSNQNVEEEKRGPKS
  IFGSSNNSFSSFPVSSAVLGEPFQASKAGVRQGCEEAVSQVEPLPSLMKGLKRKEDQDRS
  PRRHGHEPAEDSDPLSRGDHPPDKRPVRLNRPRGGTLFGRTIQDVFKSNKEVGRLGNKEA
  KKETGFVESAESDHMAIPGGNQSVLAPSRIPGVNKEEETESREKKEDSLRGTPARQSNRS
  ESTDSLGGLSPSEVTAIQCKNIPDYLNDRTILENHFGKIAKVQRIFTRRSKKLAVVHFFD
  HASAALARKKGKSLHKDMAIFWHRKKISPNKKPFSLKEKKPGDGEVSPSTEDAPFQHSPL
  GKAAGRTGASSLLNKSSPVKKPSLLKAHQFEGDSFDSASEGSEGLGPCVLSLSTLIGTVA
  ETSKEKYRLLDQRDRIMRQARVKRTDLDKARTFVGTCLDMCPEKERYMRETRSQLSVFEV
  VPGTDQVDHAAAVKEYSRSSADQEEPLPHELRPLPVLSRTMDYLVTQIMDQKEGSLRDWY
  DFVWNRTRGIRKDITQQHLCDPLTVSLIEKCTRFHIHCAHFMCEEPMSSFDAKINNENMT
  KCLQSLKEMYQDLRNKGVFCASEAEFQGYNVLLSLNKGDILREVQQFHPAVRNSSEVKFA
  VQAFAALNSNNFVRFFKLVQSASYLNACLLHCYFSQIRKDALRALNFAYTVSTQRSTIFP
  LDGVVRMLLFRDCEEATDFLTCHGLTVSDGCVELNRSAFLEPEGLSKTRKSVFITRKLTV
  SVGEIVNGGPLPPVPRHTPVCSFNSQNKYIGESLAAELPVSTQRPGSDTVGGGRGEECGV
  EPDAPLSSLPQSLPAPAPSPVPLPPVLALTPSVAPSLFQLSVQPEPPPPEPVPMYSDEDL
  AQVVDELIQEALQRDCEEVGSAGAAYAAAALGVSNAAMEDLLTAATTGILRHIAAEEVSK
  ERERREQERQRAEEERLKQERELVLSELSQGLAVELMERVMMEFVRETCSQELKNAVETD
  QRVRVARCCEDVCAHLVDLFLVEEIFQTAKETLQELQCFCKYLQRWREAVTARKKLRRQM
  RAFPAAPCCVDVSDRLRALAPSAECPIAEENLARGLLDLGHAGRLGISCTRLRRLRNKTA
  HQMKVQHFYQQLLSDVAWASLDLPSLVAEHLPGRQEHVFWKLVLVLPDVEEQSPESCGRI
  LANWLKVKFMGDEGSVDDTSSDAGGIQTLSLFNSLSSKGDQMISVNVCIKVAHGALSDGA
  IDAVETQKDLLGASGLMLLLPPKMKSEDMAEEDVYWLSALLQLKQLLQAKPFQPALPLVV
  LVPSPGGDAVEKEVEDGLMLQDLVSAKLISDYTVTEIPDTINDLQGSTKVLQAVQWLVSH
  CPHSLDLCCQTLIQYVEDGIGHEFSGRFFHDRRERRLGGLASQEPGAIIELFNSVLQFLA
  SVVSSEQLCDLSWPVTEFAEAGGSRLLPHLHWNAPEHLAWLKQAVLGFQLPQMDLPPLGA
  PWLPVCSMVVQYASQIPSSRQTQPVLQSQVENLLHRTYCRWKSKSPSPVHGAGPSVMEIP
  WDDLIALCINHKLRDWTPPRLPVTSEALSEDGQICVYFFKNDLKKYDVPLSWEQARLQTQ
  KELQLREGRLAIKPFHPSANNFPIPLLHMHRNWKRSTECAQEGRIPSTEDLMRGASAEEL
  LAQCLSSSLLLEKEENKRFEDQLQQWLSEDSGAFTDLTSLPLYLPQTLVSLSHTIEPVMK
  TSVTTSPQSDMMREQLQLSEATGTCLGERLKHLERLIRSSREEEVASELHLSALLDMVDI
• Function: [Isoform GANP]: As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores. Through the acetylation of histones, affects the assembly of nucleosomes at immunoglobulin variable region genes and promotes the recruitment and positioning of transcription complex to favor DNA cytosine deaminase AICDA/AID targeting, hence promoting somatic hypermutations ; [Isoform MCM3AP]: Binds to and acetylates the replication protein MCM3. Plays a role in the initiation of DNA replication and participates in controls that ensure that DNA replication initiates only once per cell cycle. Through the acetylation of histones, affects the assembly of nucleosomes at immunoglobulin variable region genes and promotes the recruitment and positioning of transcription complex to favor DNA cytosine deaminase AICDA/AID targeting, hence promoting somatic hypermutations.
• Tissue Specificity: Widely expressed . Up-regulated in germinal center B-cells in tonsils (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development	DIS1GSMA	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[4]
Charcot-Marie-Tooth disease type 4J	DIS23T23	Strong	Biomarker	[5]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[6]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Altered Expression	[6]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[7]
Immunodeficiency	DIS093I0	Strong	Genetic Variation	[8]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[4]
Malignant glioma	DISFXKOV	Strong	Biomarker	[2]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Neoplasm of testis	DISK4XHT	Strong	Genetic Variation	[9]
Testicular germ cell tumor	DIS5RN24	Strong	Genetic Variation	[10]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[11]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[11]
Familial periodic paralysis	DISD9YAA	moderate	Genetic Variation	[12]
Periodontitis	DISI9JOI	moderate	Genetic Variation	[13]
Hepatocellular carcinoma	DIS0J828	Disputed	Biomarker	[14]
Classic Hodgkin lymphoma	DISV1LU6	Limited	Biomarker	[15]
Lymphoma	DISN6V4S	Limited	Altered Expression	[15]
Melanocytic nevus	DISYS32D	Limited	Altered Expression	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Germinal-center associated nuclear protein (MCM3AP).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Germinal-center associated nuclear protein (MCM3AP).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Germinal-center associated nuclear protein (MCM3AP).	[20]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Germinal-center associated nuclear protein (MCM3AP).	[21]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the expression of Germinal-center associated nuclear protein (MCM3AP).	[22]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Germinal-center associated nuclear protein (MCM3AP).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Germinal-center associated nuclear protein (MCM3AP).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Germinal-center associated nuclear protein (MCM3AP).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Germinal-center associated nuclear protein (MCM3AP).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Germinal-center associated nuclear protein (MCM3AP).	[18]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Decreased expression of germinal center-associated nuclear protein is involved in chromosomal instability in malignant gliomas.Cancer Sci. 2009 Nov;100(11):2069-76. doi: 10.1111/j.1349-7006.2009.01293.x. Epub 2009 Jul 21.
• [3] GANP protein encoded on human chromosome 21/mouse chromosome 10 is associated with resistance to mammary tumor development.Cancer Sci. 2016 Apr;107(4):469-77. doi: 10.1111/cas.12883. Epub 2016 Feb 9.
• [4] MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability.Brain. 2017 Aug 1;140(8):2093-2103. doi: 10.1093/brain/awx138.
• [5] Severe Consequences of SAC3/FIG4 Phosphatase Deficiency to Phosphoinositides in Patients with Charcot-Marie-Tooth Disease Type-4J.Mol Neurobiol. 2019 Dec;56(12):8656-8667. doi: 10.1007/s12035-019-01693-8. Epub 2019 Jul 16.
• [6] Cholangiocarcinomas associated with long-term inflammation express the activation-induced cytidine deaminase and germinal center-associated nuclear protein involved in immunoglobulin V-region diversification.Int J Oncol. 2009 Aug;35(2):287-95.
• [7] Development and Validation of the Procedure-Related Neurologic Complications Risk Score for Elderly Patients with Ruptured Intracranial Aneurysm Undergoing Endovascular Treatment.World Neurosurg. 2017 Apr;100:648-657.e2. doi: 10.1016/j.wneu.2017.01.085. Epub 2017 Jan 31.
• [8] MCM3AP and POMP Mutations Cause a DNA-Repair and DNA-Damage-Signaling Defect in an Immunodeficient Child.Hum Mutat. 2016 Mar;37(3):257-68. doi: 10.1002/humu.22939. Epub 2015 Dec 30.
• [9] Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14.Nat Genet. 2013 Jun;45(6):686-9. doi: 10.1038/ng.2635. Epub 2013 May 12.
• [10] Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor.Nat Genet. 2017 Jul;49(7):1133-1140. doi: 10.1038/ng.3896. Epub 2017 Jun 12.
• [11] Impact of germinal center-associated nuclear protein polymorphisms on breast cancer risk and prognosis in a Japanese population.Breast Cancer. 2019 Sep;26(5):562-572. doi: 10.1007/s12282-019-00956-5. Epub 2019 Feb 27.
• [12] Family with primary periodic paralysis and a mutation in MCM3AP, a gene implicated in mRNA transport.Muscle Nerve. 2019 Sep;60(3):311-314. doi: 10.1002/mus.26622. Epub 2019 Jul 7.
• [13] Meta-analysis of genome-wide association studies of aggressive and chronic periodontitis identifies two novel risk loci.Eur J Hum Genet. 2019 Jan;27(1):102-113. doi: 10.1038/s41431-018-0265-5. Epub 2018 Sep 14.
• [14] LncRNA MCM3AP-AS1 Regulates Epidermal Growth Factor Receptor and Autophagy to Promote Hepatocellular Carcinoma Metastasis by Interacting with miR-455.DNA Cell Biol. 2019 Aug;38(8):857-864. doi: 10.1089/dna.2019.4770. Epub 2019 Jun 25.
• [15] Increased expression of germinal center-associated nuclear protein RNA-primase is associated with lymphomagenesis.Cancer Res. 2005 Jul 1;65(13):5925-34. doi: 10.1158/0008-5472.CAN-04-3259.
• [16] Increased expression of germinal center-associated nuclear protein (GANP) is associated with malignant transformation of melanocytes.J Dermatol Sci. 2006 Apr;42(1):55-63. doi: 10.1016/j.jdermsci.2005.12.007. Epub 2006 Jan 23.
• [17] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [18] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [19] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [20] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [21] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [22] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [23] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [24] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.