Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0SRIP4)

• DOT Name: DNA-directed DNA/RNA polymerase mu (POLM)
• Synonyms: Pol Mu; EC 2.7.7.7; Terminal transferase
• Gene Name: POLM
• Related Disease:
  Esophageal squamous cell carcinoma
  Glioma
  leukaemia
  Leukemia
  Neoplasm
  Burkitt lymphoma
  Carcinoma
  Classic Hodgkin lymphoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Lymphoma
  Ankylosing spondylitis
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Malignant soft tissue neoplasm
  Sarcoma
• UniProt ID: DPOLM_HUMAN
• PDB ID: 2DUN ; 2HTF ; 4LZD ; 4LZG ; 4M04 ; 4M0A ; 4YCX ; 4YD1 ; 4YD2 ; 5TWP ; 5TWQ ; 5TWR ; 5TWS ; 5TXX ; 5TXZ ; 5TYB ; 5TYC ; 5TYD ; 5TYE ; 5TYF ; 5TYG ; 5TYU ; 5TYV ; 5TYW ; 5TYX ; 5TYY ; 5TYZ ; 5VZ7 ; 5VZ8 ; 5VZ9 ; 5VZA ; 5VZB ; 5VZC ; 5VZD ; 5VZE ; 5VZF ; 5VZG ; 5VZH ; 5VZI ; 5W4F ; 5ZLC ; 6AEC ; 6AEH ; 6AK5 ; 6AK6 ; 6AK8 ; 6AK9 ; 6AKH ; 6IPD ; 6IPE ; 6IPF ; 6IPG ; 6IPH ; 6IPI ; 6IPJ ; 6IPK ; 6IPL ; 6IPM ; 6IPN ; 6P1M ; 6P1N ; 6P1O ; 6P1P ; 6P1Q ; 6P1R ; 6P1S ; 6P1T ; 6P1U ; 6P1V ; 6P1W ; 6VEZ ; 6VF0 ; 6VF1 ; 6VF2 ; 6VF3 ; 6VF4 ; 6VF5 ; 6VF6 ; 6VF7 ; 6VF8 ; 6VF9 ; 6VFA ; 6VFB ; 6VFC ; 6WIC ; 6WID ; 6WIE ; 7CO6 ; 7CO8 ; 7CO9 ; 7COA ; 7COB ; 7COC ; 7COD ; 7KSS ; 7KST ; 7KSU ; 7KSV ; 7KSW ; 7KSX ; 7KSY ; 7KSZ ; 7KT0 ; 7KT1 ; 7KT2 ; 7KT3 ; 7KT4 ; 7KT5 ; 7KT6 ; 7KT7 ; 7KT8 ; 7KT9 ; 7KTA ; 7KTB ; 7KTC ; 7KTD ; 7KTE ; 7KTF ; 7KTG ; 7KTH ; 7KTI ; 7KTJ ; 7KTK ; 7KTL ; 7KTM ; 7KTN
• EC Number: 2.7.7.7
• Pfam ID: PF14792 ; PF14791 ; PF10391 ; PF14716
• Sequence:
  MLPKRRRARVGSPSGDAASSTPPSTRFPGVAIYLVEPRMGRSRRAFLTGLARSKGFRVLD
  ACSSEATHVVMEETSAEEAVSWQERRMAAAPPGCTPPALLDISWLTESLGAGQPVPVECR
  HRLEVAGPRKGPLSPAWMPAYACQRPTPLTHHNTGLSEALEILAEAAGFEGSEGRLLTFC
  RAASVLKALPSPVTTLSQLQGLPHFGEHSSRVVQELLEHGVCEEVERVRRSERYQTMKLF
  TQIFGVGVKTADRWYREGLRTLDDLREQPQKLTQQQKAGLQHHQDLSTPVLRSDVDALQQ
  VVEEAVGQALPGATVTLTGGFRRGKLQGHDVDFLITHPKEGQEAGLLPRVMCRLQDQGLI
  LYHQHQHSCCESPTRLAQQSHMDAFERSFCIFRLPQPPGAAVGGSTRPCPSWKAVRVDLV
  VAPVSQFPFALLGWTGSKLFQRELRRFSRKEKGLWLNSHGLFDPEQKTFFQAASEEDIFR
  HLGLEYLPPEQRNA
• Function: Gap-filling polymerase involved in repair of DNA double-strand breaks by non-homologous end joining (NHEJ). Participates in immunoglobulin (Ig) light chain gene rearrangement in V(D)J recombination.
• Tissue Specificity: Expressed in a number of tissues. Abundant in thymus.
• KEGG Pathway: Non-homologous end-joining (hsa03450)
• Reactome Pathway: Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Biomarker	[1]
Glioma	DIS5RPEH	Definitive	Altered Expression	[2]
leukaemia	DISS7D1V	Definitive	Altered Expression	[3]
Leukemia	DISNAKFL	Definitive	Altered Expression	[3]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[5]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[6]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Lung neoplasm	DISVARNB	Strong	Genetic Variation	[8]
Lymphoma	DISN6V4S	moderate	Biomarker	[9]
Ankylosing spondylitis	DISRC6IR	Limited	Altered Expression	[10]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Limited	Altered Expression	[3]
Malignant soft tissue neoplasm	DISTC6NO	Limited	Biomarker	[9]
Sarcoma	DISZDG3U	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA-directed DNA/RNA polymerase mu (POLM).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA-directed DNA/RNA polymerase mu (POLM).	[12]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of DNA-directed DNA/RNA polymerase mu (POLM).	[13]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of DNA-directed DNA/RNA polymerase mu (POLM).	[14]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of DNA-directed DNA/RNA polymerase mu (POLM).	[12]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of DNA-directed DNA/RNA polymerase mu (POLM).	[12]
Gentamicin	DMKINJO	Approved	Gentamicin increases the expression of DNA-directed DNA/RNA polymerase mu (POLM).	[12]
MK-886	DMT0O7H	Discontinued in Phase 2	MK-886 decreases the activity of DNA-directed DNA/RNA polymerase mu (POLM).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of DNA-directed DNA/RNA polymerase mu (POLM).	[18]
Taurine	DMVW7N3	Investigative	Taurine increases the expression of DNA-directed DNA/RNA polymerase mu (POLM).	[19]

3 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-directed DNA/RNA polymerase mu (POLM).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of DNA-directed DNA/RNA polymerase mu (POLM).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of DNA-directed DNA/RNA polymerase mu (POLM).	[16]

References

• [1] Elevated DNA polymerase iota (Poli) is involved in the acquisition of aggressive phenotypes of human esophageal squamous cell cancer.Int J Clin Exp Pathol. 2015 Apr 1;8(4):3591-601. eCollection 2015.
• [2] Analysis of specialized DNA polymerases expression in human gliomas: association with prognostic significance.Neuro Oncol. 2010 Jul;12(7):679-86. doi: 10.1093/neuonc/nop074. Epub 2010 Feb 17.
• [3] Relation of "lymphoid" phenotype and response to chemotherapy incorporating vincristine-prednisolone in the acute phase of Ph1 positive leukemia.Cancer. 1979 Feb;43(2):426-34. doi: 10.1002/1097-0142(197902)43:2<426::aid-cncr2820430204>3.0.co;2-h.
• [4] Overexpression of human DNA polymerase mu (Pol mu) in a Burkitt's lymphoma cell line affects the somatic hypermutation rate.Nucleic Acids Res. 2004 Nov 1;32(19):5861-73. doi: 10.1093/nar/gkh929. Print 2004.
• [5] Overexpression of DNA polymerase iota (Pol) in esophageal squamous cell carcinoma.Cancer Sci. 2012 Aug;103(8):1574-9. doi: 10.1111/j.1349-7006.2012.02309.x. Epub 2012 May 30.
• [6] DNA polymerase mu gene expression in B-cell non-Hodgkin's lymphomas: an analysis utilizing in situ hybridization.Am J Pathol. 2002 Oct;161(4):1349-55. doi: 10.1016/s0002-9440(10)64411-2.
• [7] siRNA of DNA polymerase iota inhibits the migration and invasion in the lung cancer cell A549.Acta Biochim Biophys Sin (Shanghai). 2018 Sep 1;50(9):929-933. doi: 10.1093/abbs/gmy089.
• [8] Pol iota is a candidate for the mouse pulmonary adenoma resistance 2 locus, a major modifier of chemically induced lung neoplasia.Cancer Res. 2004 Mar 15;64(6):1924-31. doi: 10.1158/0008-5472.can-03-3080.
• [9] Pol deficiency induces moderate shortening of P53(-/-) mouse lifespan and modifies tumor spectrum.DNA Repair (Amst). 2017 Jun;54:40-45. doi: 10.1016/j.dnarep.2017.04.001. Epub 2017 Apr 10.
• [10] Expression of activation-induced cytidine deaminase splicing variants in patients with ankylosing spondylitis.Autoimmunity. 2017 Dec;50(8):435-440. doi: 10.1080/08916934.2017.1385777. Epub 2017 Sep 29.
• [11] 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.
• [12] Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2010 Oct 15;401(2):245-50. doi: 10.1016/j.bbrc.2010.09.039. Epub 2010 Sep 16.
• [13] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [14] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [15] 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.
• [16] 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.
• [17] Leukotriene biosynthesis inhibitor MK886 impedes DNA polymerase activity. Chem Res Toxicol. 2013 Feb 18;26(2):221-32. doi: 10.1021/tx300392m. Epub 2013 Jan 31.
• [18] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [19] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.