Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRHJ3GI)

• DOT Name: DNA endonuclease RBBP8 (RBBP8)
• Synonyms: EC 3.1.-.-; CtBP-interacting protein; CtIP; Retinoblastoma-binding protein 8; RBBP-8; Retinoblastoma-interacting protein and myosin-like; RIM; Sporulation in the absence of SPO11 protein 2 homolog; SAE2
• Gene Name: RBBP8
• Related Disease:
  Breast cancer
  Glaucoma/ocular hypertension
  Jawad syndrome
  Aortic aneurysm
  Bladder cancer
  Clubfoot
  Colon cancer
  Estrogen-receptor positive breast cancer
  Fanconi anemia complementation group A
  Fanconi's anemia
  Gastric cancer
  Glioblastoma multiforme
  Isolated congenital microcephaly
  Lung adenocarcinoma
  Myasthenia gravis
  Myositis disease
  Neoplasm
  Prostate neoplasm
  Retinoblastoma
  Stomach cancer
  Synovial sarcoma
  T-cell acute lymphoblastic leukaemia
  Trichohepatoenteric syndrome
  Urinary bladder cancer
  Urinary bladder neoplasm
  Carcinoma
  Plasma cell myeloma
  Seckel syndrome 2
  Small-cell lung cancer
  Seckel syndrome
  Breast carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Metastatic malignant neoplasm
  Prostate cancer
  Prostate carcinoma
  Q fever
• UniProt ID: CTIP_HUMAN
• PDB ID: 1Y98; 2L4Z; 4D2H; 7BGF
• EC Number: 3.1.-.-
• Pfam ID: PF10482 ; PF08573
• Sequence:
  MNISGSSCGSPNSADTSSDFKDLWTKLKECHDREVQGLQVKVTKLKQERILDAQRLEEFF
  TKNQQLREQQKVLHETIKVLEDRLRAGLCDRCAVTEEHMRKKQQEFENIRQQNLKLITEL
  MNERNTLQEENKKLSEQLQQKIENDQQHQAAELECEEDVIPDSPITAFSFSGVNRLRRKE
  NPHVRYIEQTHTKLEHSVCANEMRKVSKSSTHPQHNPNENEILVADTYDQSQSPMAKAHG
  TSSYTPDKSSFNLATVVAETLGLGVQEESETQGPMSPLGDELYHCLEGNHKKQPFEESTR
  NTEDSLRFSDSTSKTPPQEELPTRVSSPVFGATSSIKSGLDLNTSLSPSLLQPGKKKHLK
  TLPFSNTCISRLEKTRSKSEDSALFTHHSLGSEVNKIIIQSSNKQILINKNISESLGEQN
  RTEYGKDSNTDKHLEPLKSLGGRTSKRKKTEEESEHEVSCPQASFDKENAFPFPMDNQFS
  MNGDCVMDKPLDLSDRFSAIQRQEKSQGSETSKNKFRQVTLYEALKTIPKGFSSSRKASD
  GNCTLPKDSPGEPCSQECIILQPLNKCSPDNKPSLQIKEENAVFKIPLRPRESLETENVL
  DDIKSAGSHEPIKIQTRSDHGGCELASVLQLNPCRTGKIKSLQNNQDVSFENIQWSIDPG
  ADLSQYKMDVTVIDTKDGSQSKLGGETVDMDCTLVSETVLLKMKKQEQKGEKSSNEERKM
  NDSLEDMFDRTTHEEYESCLADSFSQAADEEEELSTATKKLHTHGDKQDKVKQKAFVEPY
  FKGDERETSLQNFPHIEVVRKKEERRKLLGHTCKECEIYYADMPAEEREKKLASCSRHRF
  RYIPPNTPENFWEVGFPSTQTCMERGYIKEDLDPCPRPKRRQPYNAIFSPKGKEQKT
• Function: Endonuclease that cooperates with the MRE11-RAD50-NBN (MRN) complex in DNA-end resection, the first step of double-strand break (DSB) repair through the homologous recombination (HR) pathway. HR is restricted to S and G2 phases of the cell cycle and preferentially repairs DSBs resulting from replication fork collapse. Key determinant of DSB repair pathway choice, as it commits cells to HR by preventing classical non-homologous end-joining (NHEJ). Functions downstream of the MRN complex and ATM, promotes ATR activation and its recruitment to DSBs in the S/G2 phase facilitating the generation of ssDNA. Component of the BRCA1-RBBP8 complex that regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage. During immunoglobulin heavy chain class-switch recombination, promotes microhomology-mediated alternative end joining (A-NHEJ) and plays an essential role in chromosomal translocations. Binds preferentially to DNA Y-junctions and to DNA substrates with blocked ends and promotes intermolecular DNA bridging.
• Tissue Specificity: Expressed in ER-positive breast cancer lines, but tends to be down-regulated ER-negative cells (at protein level).
• KEGG Pathway: Homologous recombi.tion (hsa03440)
• Reactome Pathway:
  HDR through MMEJ (alt-NHEJ) (R-HSA-5685939)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  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)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  Meiotic recombination (R-HSA-912446)
  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 RAD51 (R-HSA-9709570)
  Impaired BRCA2 binding to PALB2 (R-HSA-9709603)
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Glaucoma/ocular hypertension	DISLBXBY	Definitive	Biomarker	[2]
Jawad syndrome	DIS6USMG	Definitive	Autosomal recessive	[3]
Aortic aneurysm	DISQ5KRA	Strong	Genetic Variation	[4]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[5]
Clubfoot	DISLXT4S	Strong	Genetic Variation	[3]
Colon cancer	DISVC52G	Strong	Genetic Variation	[6]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[7]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[8]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[8]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[9]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[10]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[3]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[11]
Myasthenia gravis	DISELRCI	Strong	Genetic Variation	[12]
Myositis disease	DISCIXF0	Strong	Genetic Variation	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[15]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[16]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[9]
Synovial sarcoma	DISEZJS7	Strong	Altered Expression	[17]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[18]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[19]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[5]
Carcinoma	DISH9F1N	moderate	Altered Expression	[10]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[20]
Seckel syndrome 2	DISOV2MU	Moderate	Autosomal recessive	[21]
Small-cell lung cancer	DISK3LZD	moderate	Altered Expression	[22]
Seckel syndrome	DISEVUBA	Supportive	Autosomal recessive	[23]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[24]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[25]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[26]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[26]
Prostate cancer	DISF190Y	Limited	Altered Expression	[15]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[15]
Q fever	DISK1S90	Limited	Biomarker	[27]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	DNA endonuclease RBBP8 (RBBP8) affects the response to substance of Mitoxantrone.	[50]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of DNA endonuclease RBBP8 (RBBP8).	[28]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA endonuclease RBBP8 (RBBP8).	[29]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA endonuclease RBBP8 (RBBP8).	[30]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA endonuclease RBBP8 (RBBP8).	[31]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA endonuclease RBBP8 (RBBP8).	[32]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA endonuclease RBBP8 (RBBP8).	[33]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of DNA endonuclease RBBP8 (RBBP8).	[34]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA endonuclease RBBP8 (RBBP8).	[35]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA endonuclease RBBP8 (RBBP8).	[35]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of DNA endonuclease RBBP8 (RBBP8).	[36]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of DNA endonuclease RBBP8 (RBBP8).	[37]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of DNA endonuclease RBBP8 (RBBP8).	[38]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of DNA endonuclease RBBP8 (RBBP8).	[39]
Estrone	DM5T6US	Approved	Estrone increases the expression of DNA endonuclease RBBP8 (RBBP8).	[37]
Mestranol	DMG3F94	Approved	Mestranol increases the expression of DNA endonuclease RBBP8 (RBBP8).	[37]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of DNA endonuclease RBBP8 (RBBP8).	[33]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of DNA endonuclease RBBP8 (RBBP8).	[40]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of DNA endonuclease RBBP8 (RBBP8).	[41]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA endonuclease RBBP8 (RBBP8).	[42]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DNA endonuclease RBBP8 (RBBP8).	[44]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL increases the expression of DNA endonuclease RBBP8 (RBBP8).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of DNA endonuclease RBBP8 (RBBP8).	[47]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA endonuclease RBBP8 (RBBP8).	[48]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of DNA endonuclease RBBP8 (RBBP8).	[49]
Daidzein	DMRFTJX	Investigative	Daidzein increases the expression of DNA endonuclease RBBP8 (RBBP8).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 affects the sumoylation of DNA endonuclease RBBP8 (RBBP8).	[43]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of DNA endonuclease RBBP8 (RBBP8).	[45]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA endonuclease RBBP8 (RBBP8).	[46]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of DNA endonuclease RBBP8 (RBBP8).	[45]

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