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

DOT Name Histone-lysine N-methyltransferase PRDM9 (PRDM9)
Synonyms
PR domain zinc finger protein 9; PR domain-containing protein 9; Protein-lysine N-methyltransferase PRDM9; EC 2.1.1.-; -lysine36 N-trimethyltransferase PRDM9; EC 2.1.1.359; -lysine4 N-trimethyltransferase PRDM9; EC 2.1.1.354; -lysine9 N-trimethyltransferase PRDM9; EC 2.1.1.355; -N-methyl-L-lysine20 N-methyltransferase PRDM9; EC 2.1.1.362; -lysine20 N-methyltransferase PRDM9; EC 2.1.1.361
Gene Name PRDM9
Related Disease
Azoospermia ( )
Childhood acute lymphoblastic leukemia ( )
Clear cell renal carcinoma ( )
DiGeorge syndrome ( )
Head-neck squamous cell carcinoma ( )
Male infertility ( )
Neoplasm ( )
Oligospermia ( )
Prader-Willi syndrome ( )
Shprintzen-Goldberg syndrome ( )
Velocardiofacial syndrome ( )
Acute lymphocytic leukaemia ( )
Advanced cancer ( )
Cryptorchidism ( )
UniProt ID
PRDM9_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
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PDB ID
4IJD; 5EGB; 5EH2; 5EI9; 6NM4
EC Number
2.1.1.-; 2.1.1.354; 2.1.1.355; 2.1.1.359; 2.1.1.361; 2.1.1.362
Pfam ID
PF01352 ; PF21549 ; PF09514 ; PF00096 ; PF21225
Sequence
MSPEKSQEESPEEDTERTERKPMVKDAFKDISIYFTKEEWAEMGDWEKTRYRNVKRNYNA
LITIGLRATRPAFMCHRRQAIKLQVDDTEDSDEEWTPRQQVKPPWMALRVEQRKHQKGMP
KASFSNESSLKELSRTANLLNASGSEQAQKPVSPSGEASTSGQHSRLKLELRKKETERKM
YSLRERKGHAYKEVSEPQDDDYLYCEMCQNFFIDSCAAHGPPTFVKDSAVDKGHPNRSAL
SLPPGLRIGPSGIPQAGLGVWNEASDLPLGLHFGPYEGRITEDEEAANNGYSWLITKGRN
CYEYVDGKDKSWANWMRYVNCARDDEEQNLVAFQYHRQIFYRTCRVIRPGCELLVWYGDE
YGQELGIKWGSKWKKELMAGREPKPEIHPCPSCCLAFSSQKFLSQHVERNHSSQNFPGPS
ARKLLQPENPCPGDQNQEQQYPDPHSRNDKTKGQEIKERSKLLNKRTWQREISRAFSSPP
KGQMGSCRVGKRIMEEESRTGQKVNPGNTGKLFVGVGISRIAKVKYGECGQGFSVKSDVI
THQRTHTGEKLYVCRECGRGFSWKSHLLIHQRIHTGEKPYVCRECGRGFSWQSVLLTHQR
THTGEKPYVCRECGRGFSRQSVLLTHQRRHTGEKPYVCRECGRGFSRQSVLLTHQRRHTG
EKPYVCRECGRGFSWQSVLLTHQRTHTGEKPYVCRECGRGFSWQSVLLTHQRTHTGEKPY
VCRECGRGFSNKSHLLRHQRTHTGEKPYVCRECGRGFRDKSHLLRHQRTHTGEKPYVCRE
CGRGFRDKSNLLSHQRTHTGEKPYVCRECGRGFSNKSHLLRHQRTHTGEKPYVCRECGRG
FRNKSHLLRHQRTHTGEKPYVCRECGRGFSDRSSLCYHQRTHTGEKPYVCREDE
Function
Histone methyltransferase that sequentially mono-, di-, and tri-methylates both 'Lys-4' (H3K4) and 'Lys-36' (H3K36) of histone H3 to produce respectively trimethylated 'Lys-4' (H3K4me3) and trimethylated 'Lys-36' (H3K36me3) histone H3 and plays a key role in meiotic prophase by determining hotspot localization thereby promoting meiotic recombination. Can also methylate all four core histones with H3 being the best substrate and the most highly modified. Is also able, on one hand, to mono and di-methylate H4K20 and on other hand to trimethylate H3K9 with the di-methylated H3K9 as the best substrate. During meiotic prophase, binds specific DNA sequences through its zinc finger domains thereby determining hotspot localization where it promotes local H3K4me3 and H3K36me3 enrichment on the same nucleosomes through its histone methyltransferase activity. Thereby promotes double-stranded breaks (DSB) formation, at this subset of PRDM9-binding sites, that initiates meiotic recombination for the proper meiotic progression. During meiotic progression hotspot-bound PRDM9 interacts with several complexes; in early leptonema binds CDYL and EHMT2 followed by EWSR1 and CXXC1 by the end of leptonema. EWSR1 joins PRDM9 with the chromosomal axis through REC8. In this way, controls the DSB repair pathway, pairing of homologous chromosomes and sex body formation. Moreover plays a central role in the transcriptional activation of genes during early meiotic prophase thanks to H3K4me3 and H3K36me3 enrichment that represents a specific tag for epigenetic transcriptional activation. In addition performs automethylation. Acetylation and phosphorylation of histone H3 attenuate or prevent histone H3 methylation.
KEGG Pathway
Lysine degradation (hsa00310 )
Metabolic pathways (hsa01100 )
Reactome Pathway
Meiotic recombination (R-HSA-912446 )
PKMTs methylate histone lysines (R-HSA-3214841 )
BioCyc Pathway
MetaCyc:HS09047-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Azoospermia DIS94181 Strong Biomarker [1]
Childhood acute lymphoblastic leukemia DISJ5D6U Strong Genetic Variation [2]
Clear cell renal carcinoma DISBXRFJ Strong Biomarker [3]
DiGeorge syndrome DIST1RKO Strong Genetic Variation [4]
Head-neck squamous cell carcinoma DISF7P24 Strong Genetic Variation [5]
Male infertility DISY3YZZ Strong Genetic Variation [6]
Neoplasm DISZKGEW Strong Posttranslational Modification [7]
Oligospermia DIS6YJF3 Strong Genetic Variation [8]
Prader-Willi syndrome DISYWMLU Strong Genetic Variation [4]
Shprintzen-Goldberg syndrome DISQH6P3 Strong Genetic Variation [4]
Velocardiofacial syndrome DISOSBTY Strong Genetic Variation [4]
Acute lymphocytic leukaemia DISPX75S Disputed Genetic Variation [2]
Advanced cancer DISAT1Z9 Limited Biomarker [9]
Cryptorchidism DISYUD2P Limited Biomarker [10]
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⏷ Show the Full List of 14 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 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 Histone-lysine N-methyltransferase PRDM9 (PRDM9). [11]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the methylation of Histone-lysine N-methyltransferase PRDM9 (PRDM9). [12]
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References

1 Two single nucleotide polymorphisms in PRDM9 (MEISETZ) gene may be a genetic risk factor for Japanese patients with azoospermia by meiotic arrest.J Assist Reprod Genet. 2008 Nov-Dec;25(11-12):553-7. doi: 10.1007/s10815-008-9270-x. Epub 2008 Oct 22.
2 Whole-exome sequencing of a rare case of familial childhood acute lymphoblastic leukemia reveals putative predisposing mutations in Fanconi anemia genes.BMC Cancer. 2015 Jul 23;15:539. doi: 10.1186/s12885-015-1549-6.
3 EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming.Cancer Res. 2017 Dec 1;77(23):6651-6666. doi: 10.1158/0008-5472.CAN-17-0899. Epub 2017 Oct 4.
4 Evaluation of PRDM9 variation as a risk factor for recurrent genomic disorders and chromosomal non-disjunction.Hum Genet. 2012 Sep;131(9):1519-24. doi: 10.1007/s00439-012-1180-4. Epub 2012 May 30.
5 The non-coding landscape of head and neck squamous cell carcinoma.Oncotarget. 2016 Aug 9;7(32):51211-51222. doi: 10.18632/oncotarget.9979.
6 Bos taurus-indicus hybridization correlates with intralocus sexual-conflict effects of PRDM9 on male and female fertility in Holstein cattle.BMC Genet. 2019 Aug 28;20(1):71. doi: 10.1186/s12863-019-0773-5.
7 Overexpression of enhance of Zeste homolog 2 (EZH2) in endometrial carcinoma: An NRG Oncology/Gynecologic Oncology Group Study.Gynecol Oncol. 2020 Feb;156(2):423-429. doi: 10.1016/j.ygyno.2019.12.003. Epub 2019 Dec 13.
8 PRDM9 gene polymorphism may not be associated with defective spermatogenesis in the Chinese Han population.Syst Biol Reprod Med. 2013 Feb;59(1):38-41. doi: 10.3109/19396368.2012.723793. Epub 2012 Nov 29.
9 C-terminal domain of SMYD3 serves as a unique HSP90-regulated motif in oncogenesis.Oncotarget. 2015 Feb 28;6(6):4005-19. doi: 10.18632/oncotarget.2970.
10 ENU mutagenesis in mice identifies candidate genes for hypogonadism.Mamm Genome. 2012 Jun;23(5-6):346-55. doi: 10.1007/s00335-011-9388-5. Epub 2012 Jan 19.
11 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.
12 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.