Details of Drug Off-Target (DOT)

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

• DOT Name: Ribosome maturation protein SBDS (SBDS)
• Synonyms: Shwachman-Bodian-Diamond syndrome protein
• Gene Name: SBDS
• Related Disease:
  Shwachman-Diamond syndrome
  Shwachman-Diamond syndrome 1
  Acquired aplastic anemia
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Childhood myelodysplastic syndrome
  Common variable immunodeficiency
  Diamond-Blackfan anemia
  Dyskeratosis congenita
  Exocrine pancreatic insufficiency
  Hematologic disease
  Idiopathic aplastic anemia
  Myelodysplastic syndrome
  Pancreas disorder
  Aplastic anemia
  Leukopenia
  Osteochondrodysplasia
  Skeletal dysplasia
  leukaemia
  Leukemia
  Osteoporosis
  Pancytopenia
• UniProt ID: SBDS_HUMAN
• PDB ID: 2KDO; 2L9N; 5AN9; 5ANB; 5ANC; 6QKL
• Pfam ID: PF01172 ; PF20268 ; PF09377
• Sequence:
  MSIFTPTNQIRLTNVAVVRMKRAGKRFEIACYKNKVVGWRSGVEKDLDEVLQTHSVFVNV
  SKGQVAKKEDLISAFGTDDQTEICKQILTKGEVQVSDKERHTQLEQMFRDIATIVADKCV
  NPETKRPYTVILIERAMKDIHYSVKTNKSTKQQALEVIKQLKEKMKIERAHMRLRFILPV
  NEGKKLKEKLKPLIKVIESEDYGQQLEIVCLIDPGCFREIDELIKKETKGKGSLEVLNLK
  DVEEGDEKFE
• Function: Required for the assembly of mature ribosomes and ribosome biogenesis. Together with EFL1, triggers the GTP-dependent release of EIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating EIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export. Required for normal levels of protein synthesis. May play a role in cellular stress resistance. May play a role in cellular response to DNA damage. May play a role in cell proliferation.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Shwachman-Diamond syndrome	DISW57NW	Definitive	Autosomal recessive	[1]
Shwachman-Diamond syndrome 1	DISRH3TQ	Definitive	Autosomal recessive	[2]
Acquired aplastic anemia	DISCMKMX	Strong	Genetic Variation	[3]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[5]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Altered Expression	[6]
Common variable immunodeficiency	DISHE7JQ	Strong	Genetic Variation	[7]
Diamond-Blackfan anemia	DISI2SNW	Strong	Genetic Variation	[7]
Dyskeratosis congenita	DISSXV0K	Strong	Biomarker	[8]
Exocrine pancreatic insufficiency	DISCZYU2	Strong	Genetic Variation	[9]
Hematologic disease	DIS9XD9A	Strong	Biomarker	[10]
Idiopathic aplastic anemia	DISVFTJ9	Strong	SusceptibilityMutation	[3]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[4]
Pancreas disorder	DISDH7NI	Strong	Biomarker	[10]
Aplastic anemia	DISJRSC0	moderate	Genetic Variation	[3]
Leukopenia	DISJMBMM	moderate	Genetic Variation	[11]
Osteochondrodysplasia	DIS9SPWW	moderate	Genetic Variation	[9]
Skeletal dysplasia	DIS5Z8U6	moderate	Genetic Variation	[9]
leukaemia	DISS7D1V	Limited	Genetic Variation	[12]
Leukemia	DISNAKFL	Limited	Genetic Variation	[12]
Osteoporosis	DISF2JE0	Limited	Genetic Variation	[13]
Pancytopenia	DISVKEHV	Limited	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ribosome maturation protein SBDS (SBDS).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Ribosome maturation protein SBDS (SBDS).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ribosome maturation protein SBDS (SBDS).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ribosome maturation protein SBDS (SBDS).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Ribosome maturation protein SBDS (SBDS).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ribosome maturation protein SBDS (SBDS).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ribosome maturation protein SBDS (SBDS).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ribosome maturation protein SBDS (SBDS).	[22]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Ribosome maturation protein SBDS (SBDS).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ribosome maturation protein SBDS (SBDS).	[24]

1 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 Ribosome maturation protein SBDS (SBDS).	[19]

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] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] Mutations in the SBDS gene in acquired aplastic anemia.Blood. 2007 Aug 15;110(4):1141-6. doi: 10.1182/blood-2007-03-080044. Epub 2007 May 3.
• [4] Germline Genetic Predisposition to Hematologic Malignancy.J Clin Oncol. 2017 Mar 20;35(9):1018-1028. doi: 10.1200/JCO.2016.70.8644. Epub 2017 Feb 13.
• [5] Totipotent stem cells bearing del(20q) maintain multipotential differentiation in Shwachman Diamond syndrome.Br J Haematol. 2009 Jan;144(1):116-9. doi: 10.1111/j.1365-2141.2008.07448.x. Epub 2008 Nov 11.
• [6] Impaired expression of DICER, DROSHA, SBDS and some microRNAs in mesenchymal stromal cells from myelodysplastic syndrome patients.Haematologica. 2012 Aug;97(8):1218-24. doi: 10.3324/haematol.2011.054437. Epub 2012 Feb 27.
• [7] Do ribosomopathies explain some cases of common variable immunodeficiency?.Clin Exp Immunol. 2011 Jan;163(1):96-103. doi: 10.1111/j.1365-2249.2010.04280.x. Epub 2010 Nov 9.
• [8] Phylogeny, sequence conservation, and functional complementation of the SBDS protein family.Genomics. 2006 Jun;87(6):758-71. doi: 10.1016/j.ygeno.2006.01.010. Epub 2006 Mar 10.
• [9] The Shwachman-Bodian-Diamond syndrome gene mutations cause a neonatal form of spondylometaphysial dysplasia (SMD) resembling SMD Sedaghatian type.J Med Genet. 2007 Apr;44(4):e73. doi: 10.1136/jmg.2006.043869.
• [10] Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation.Clin Genet. 2011 May;79(5):448-58. doi: 10.1111/j.1399-0004.2010.01468.x.
• [11] Shwachman-Bodian-Diamond syndrome (SBDS) protein deficiency impairs translation re-initiation from C/EBP and C/EBP mRNAs.Nucleic Acids Res. 2016 May 19;44(9):4134-46. doi: 10.1093/nar/gkw005. Epub 2016 Jan 13.
• [12] Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome.Genes Dev. 2011 May 1;25(9):917-29. doi: 10.1101/gad.623011.
• [13] Shwachman-Diamond syndrome is associated with low-turnover osteoporosis.Bone. 2007 Dec;41(6):965-72. doi: 10.1016/j.bone.2007.08.035. Epub 2007 Sep 5.
• [14] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [15] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [18] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [19] 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.
• [20] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [23] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [24] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.