Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKOU5XN)

• DOT Name: DNA repair protein RAD51 homolog 4 (RAD51D)
• Synonyms: R51H3; RAD51 homolog D; RAD51-like protein 3; TRAD
• Gene Name: RAD51D
• Related Disease:
  Breast-ovarian cancer, familial, susceptibility to, 3
  Colorectal carcinoma
  Neoplasm
  Breast neoplasm
  Breast-ovarian cancer, familial, susceptibility to, 4
  Fanconi anemia complementation group A
  Fanconi's anemia
  Hepatocellular carcinoma
  Triple negative breast cancer
  Bloom syndrome
  Fallopian tube carcinoma
  Hereditary breast ovarian cancer syndrome
  Hereditary neoplastic syndrome
  Advanced cancer
  Hereditary breast carcinoma
• UniProt ID: RA51D_HUMAN
• PDB ID: 2KZ3; 8FAZ; 8GBJ; 8OUY; 8OUZ
• Pfam ID: PF08423 ; PF21794
• Sequence:
  MGVLRVGLCPGLTEEMIQLLRSHRIKTVVDLVSADLEEVAQKCGLSYKALVALRRVLLAQ
  FSAFPVNGADLYEELKTSTAILSTGIGSLDKLLDAGLYTGEVTEIVGGPGSGKTQVCLCM
  AANVAHGLQQNVLYVDSNGGLTASRLLQLLQAKTQDEEEQAEALRRIQVVHAFDIFQMLD
  VLQELRGTVAQQVTGSSGTVKVVVVDSVTAVVSPLLGGQQREGLALMMQLARELKTLARD
  LGMAVVVTNHITRDRDSGRLKPALGRSWSFVPSTRILLDTIEGAGASGGRRMACLAKSSR
  QPTGFQEMVDIGTWGTSEQSATLQGDQT
• Function: Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. Bind to single-stranded DNA (ssDNA) and has DNA-dependent ATPase activity. Part of the RAD51 paralog protein complex BCDX2 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, BCDX2 acts downstream of BRCA2 recruitment and upstream of RAD51 recruitment. BCDX2 binds predominantly to the intersection of the four duplex arms of the Holliday junction and to junction of replication forks. The BCDX2 complex was originally reported to bind single-stranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA. Involved in telomere maintenance. The BCDX2 subcomplex XRCC2:RAD51D can stimulate Holliday junction resolution by BLM.
• Tissue Specificity: Expressed in colon, prostate, spleen, testis, ovary, thymus and small intestine. Weakly expressed in leukocytes.
• KEGG Pathway: Homologous recombi.tion (hsa03440)
• Reactome Pathway:
  Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) (R-HSA-5693554)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)
  Homologous DNA Pairing and Strand Exchange (R-HSA-5693579)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  Defective homologous recombination repair (HRR) due to BRCA1 loss of function (R-HSA-9701192)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function (R-HSA-9704331)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function (R-HSA-9704646)
  Impaired BRCA2 binding to PALB2 (R-HSA-9709603)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast-ovarian cancer, familial, susceptibility to, 3	DISHX3FO	Definitive	Autosomal dominant	[1]
Colorectal carcinoma	DIS5PYL0	Definitive	Genetic Variation	[2]
Neoplasm	DISZKGEW	Definitive	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[4]
Breast-ovarian cancer, familial, susceptibility to, 4	DIS5QMRP	Strong	Autosomal dominant	[5]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Genetic Variation	[6]
Fanconi's anemia	DISGW6Q8	Strong	Genetic Variation	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[7]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[8]
Bloom syndrome	DISKXQ7J	moderate	Biomarker	[9]
Fallopian tube carcinoma	DIST7A80	moderate	Biomarker	[10]
Hereditary breast ovarian cancer syndrome	DISWDUGU	Supportive	Autosomal dominant	[11]
Hereditary neoplastic syndrome	DISGXLG5	Disputed	Genetic Variation	[12]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[13]
Hereditary breast carcinoma	DISAEZT5	Limited	Autosomal dominant	[14]

6 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 repair protein RAD51 homolog 4 (RAD51D).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA repair protein RAD51 homolog 4 (RAD51D).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DNA repair protein RAD51 homolog 4 (RAD51D).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of DNA repair protein RAD51 homolog 4 (RAD51D).	[18]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of DNA repair protein RAD51 homolog 4 (RAD51D).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA repair protein RAD51 homolog 4 (RAD51D).	[20]

References

• [1] Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. J Clin Oncol. 2015 Sep 10;33(26):2901-7. doi: 10.1200/JCO.2015.61.2408. Epub 2015 Aug 10.
• [2] A Finnish founder mutation in RAD51D: analysis in breast, ovarian, prostate, and colorectal cancer.J Med Genet. 2012 Jul;49(7):429-32. doi: 10.1136/jmedgenet-2012-100852. Epub 2012 May 31.
• [3] Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-B.Mol Ther Oncolytics. 2017 Oct 26;7:76-85. doi: 10.1016/j.omto.2017.10.003. eCollection 2017 Dec 15.
• [4] The variant E233G of the RAD51D gene could be a low-penetrance allele in high-risk breast cancer families without BRCA1/2 mutations.Int J Cancer. 2004 Jul 20;110(6):845-9. doi: 10.1002/ijc.20169.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] Differential Requirements for the RAD51 Paralogs in Genome Repair and Maintenance in Human Cells.PLoS Genet. 2019 Oct 4;15(10):e1008355. doi: 10.1371/journal.pgen.1008355. eCollection 2019 Oct.
• [7] Association between polymorphisms in MicroRNA target sites of RAD51D genes and risk of hepatocellular carcinoma.Cancer Med. 2019 May;8(5):2545-2552. doi: 10.1002/cam4.2068. Epub 2019 Mar 18.
• [8] Associations between RAD51D germline mutations and breast cancer risk and survival in BRCA1/2-negative breast cancers.Ann Oncol. 2018 Oct 1;29(10):2046-2051. doi: 10.1093/annonc/mdy338.
• [9] Functional interaction between the Bloom's syndrome helicase and the RAD51 paralog, RAD51L3 (RAD51D).J Biol Chem. 2003 Nov 28;278(48):48357-66. doi: 10.1074/jbc.M308838200. Epub 2003 Sep 15.
• [10] Loss of function germline mutations in RAD51D in women with ovarian carcinoma.Gynecol Oncol. 2012 Dec;127(3):552-5. doi: 10.1016/j.ygyno.2012.09.009. Epub 2012 Sep 14.
• [11] Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet. 2011 Aug 7;43(9):879-882. doi: 10.1038/ng.893.
• [12] Detection of Germline Mutations in Patients with Epithelial Ovarian Cancer Using Multi-gene Panels: Beyond BRCA1/2.Cancer Res Treat. 2018 Jul;50(3):917-925. doi: 10.4143/crt.2017.220. Epub 2017 Sep 27.
• [13] Clinical utility of hereditary cancer panel testing: Impact of PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D results on patient management and adherence to provider recommendations.Cancer. 2020 Feb 1;126(3):549-558. doi: 10.1002/cncr.32572. Epub 2019 Nov 4.
• [14] 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.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [18] 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.
• [19] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [20] Chlorophyllin significantly reduces benzo[a]pyrene-DNA adduct formation and alters cytochrome P450 1A1 and 1B1 expression and EROD activity in normal human mammary epithelial cells. Environ Mol Mutagen. 2009 Mar;50(2):134-44.