Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT76POLP)

• DOT Name: Replication protein A 70 kDa DNA-binding subunit (RPA1)
• Synonyms: RP-A p70; Replication factor A protein 1; RF-A protein 1; Single-stranded DNA-binding protein
• Gene Name: RPA1
• Related Disease:
  Spinocerebellar ataxia type 1
  Alzheimer disease
  Breast neoplasm
  Carcinoma of esophagus
  Colorectal carcinoma
  Differentiated thyroid carcinoma
  Esophageal cancer
  Glioblastoma multiforme
  Lupus
  Multiple sclerosis
  Neoplasm
  Neoplasm of esophagus
  Nervous system disease
  Non-small-cell lung cancer
  Plasma cell myeloma
  Psoriasis
  Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6
  Schizophrenia
  Shwachman-Diamond syndrome
  Skin neoplasm
  Triple negative breast cancer
  Coronary atherosclerosis
  Coronary heart disease
  Lung cancer
  Lung carcinoma
  Small lymphocytic lymphoma
  Leishmaniasis
  Advanced cancer
  Carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Fanconi anemia complementation group J
  Female hypogonadism
  Hepatocellular carcinoma
  Liver cancer
  Malignant tumor of nasopharynx
  Nasopharyngeal carcinoma
• UniProt ID: RFA1_HUMAN
• PDB ID: 1EWI ; 1FGU ; 1JMC ; 1L1O ; 2B29 ; 2B3G ; 4IJH ; 4IJL ; 4IPC ; 4IPD ; 4IPG ; 4IPH ; 4LUO ; 4LUV ; 4LUZ ; 4LW1 ; 4LWC ; 4NB3 ; 4O0A ; 4R4C ; 4R4I ; 4R4O ; 4R4Q ; 4R4T ; 5E7N ; 5EAY ; 5N85 ; 5N8A ; 7XUT ; 7XUV ; 7XUW ; 7XV0 ; 7XV1 ; 7XV4 ; 8JZV ; 8JZY ; 8K00
• Pfam ID: PF04057 ; PF08646 ; PF16900 ; PF01336
• Sequence:
  MVGQLSEGAIAAIMQKGDTNIKPILQVINIRPITTGNSPPRYRLLMSDGLNTLSSFMLAT
  QLNPLVEEEQLSSNCVCQIHRFIVNTLKDGRRVVILMELEVLKSAEAVGVKIGNPVPYNE
  GLGQPQVAPPAPAASPAASSRPQPQNGSSGMGSTVSKAYGASKTFGKAAGPSLSHTSGGT
  QSKVVPIASLTPYQSKWTICARVTNKSQIRTWSNSRGEGKLFSLELVDESGEIRATAFNE
  QVDKFFPLIEVNKVYYFSKGTLKIANKQFTAVKNDYEMTFNNETSVMPCEDDHHLPTVQF
  DFTGIDDLENKSKDSLVDIIGICKSYEDATKITVRSNNREVAKRNIYLMDTSGKVVTATL
  WGEDADKFDGSRQPVLAIKGARVSDFGGRSLSVLSSSTIIANPDIPEAYKLRGWFDAEGQ
  ALDGVSISDLKSGGVGGSNTNWKTLYEVKSENLGQGDKPDYFSSVATVVYLRKENCMYQA
  CPTQDCNKKVIDQQNGLYRCEKCDTEFPNFKYRMILSVNIADFQENQWVTCFQESAEAIL
  GQNAAYLGELKDKNEQAFEEVFQNANFRSFIFRVRVKVETYNDESRIKATVMDVKPVDYR
  EYGRRLVMSIRRSALM
• Function: As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates, that form during DNA replication or upon DNA stress. It prevents their reannealing and in parallel, recruits and activates different proteins and complexes involved in DNA metabolism. Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage. In the cellular response to DNA damage, the RPA complex controls DNA repair and DNA damage checkpoint activation. Through recruitment of ATRIP activates the ATR kinase a master regulator of the DNA damage response. It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin in response to DNA damage. Also recruits to sites of DNA damage proteins like XPA and XPG that are involved in nucleotide excision repair and is required for this mechanism of DNA repair. Also plays a role in base excision repair (BER) probably through interaction with UNG. Also recruits SMARCAL1/HARP, which is involved in replication fork restart, to sites of DNA damage. Plays a role in telomere maintenance. As part of the alternative replication protein A complex, aRPA, binds single-stranded DNA and probably plays a role in DNA repair. Compared to the RPA2-containing, canonical RPA complex, may not support chromosomal DNA replication and cell cycle progression through S-phase. The aRPA may not promote efficient priming by DNA polymerase alpha but could support DNA synthesis by polymerase delta in presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange.
• KEGG Pathway:
  D. replication (hsa03030)
  Nucleotide excision repair (hsa03420)
  Mismatch repair (hsa03430)
  Homologous recombi.tion (hsa03440)
  Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Recognition of DNA damage by PCNA-containing replication complex (R-HSA-110314)
  Translesion Synthesis by POLH (R-HSA-110320)
  Removal of the Flap Intermediate from the C-strand (R-HSA-174437)
  Activation of ATR in response to replication stress (R-HSA-176187)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  HSF1 activation (R-HSA-3371511)
  Mismatch repair (MMR) directed by MSH2 (R-HSA-5358565)
  Mismatch repair (MMR) directed by MSH2 (R-HSA-5358606)
  PCNA-Dependent Long Patch Base Excision Repair (R-HSA-5651801)
  Translesion synthesis by POLK (R-HSA-5655862)
  Translesion synthesis by POLI (R-HSA-5656121)
  Termination of translesion DNA synthesis (R-HSA-5656169)
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)
  Gap-filling DNA repair synthesis and ligation in GG-NER (R-HSA-5696397)
  Dual Incision in GG-NER (R-HSA-5696400)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  Fanconi Anemia Pathway (R-HSA-6783310)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  Activation of the pre-replicative complex (R-HSA-68962)
  Removal of the Flap Intermediate (R-HSA-69166)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Meiotic recombination (R-HSA-912446)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Translesion synthesis by REV1 (R-HSA-110312)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spinocerebellar ataxia type 1	DISF7BO2	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Differentiated thyroid carcinoma	DIS1V20Y	Strong	Genetic Variation	[6]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[7]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[8]
Lupus	DISOKJWA	Strong	Biomarker	[9]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[7]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[11]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[12]
Psoriasis	DIS59VMN	Strong	Biomarker	[9]
Pulmonary fibrosis and/or bone marrow failure, telomere-related, 6	DISOGQIB	Strong	Autosomal dominant	[13]
Schizophrenia	DISSRV2N	Strong	Biomarker	[9]
Shwachman-Diamond syndrome	DISW57NW	Strong	Biomarker	[14]
Skin neoplasm	DIS16DDV	Strong	Altered Expression	[15]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[16]
Coronary atherosclerosis	DISKNDYU	moderate	Genetic Variation	[17]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[17]
Lung cancer	DISCM4YA	moderate	Altered Expression	[18]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[18]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[19]
Leishmaniasis	DISABTW7	Disputed	Biomarker	[20]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[21]
Carcinoma	DISH9F1N	Limited	Biomarker	[4]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[4]
Fanconi anemia complementation group J	DISWACKN	Limited	Genetic Variation	[22]
Female hypogonadism	DISWASB4	Limited	Genetic Variation	[23]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[4]
Liver cancer	DISDE4BI	Limited	Biomarker	[4]
Malignant tumor of nasopharynx	DISTGIGF	Limited	Altered Expression	[24]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[24]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Replication protein A 70 kDa DNA-binding subunit (RPA1) affects the response to substance of Topotecan.	[53]
Capecitabine	DMTS85L	Approved	Replication protein A 70 kDa DNA-binding subunit (RPA1) decreases the response to substance of Capecitabine.	[54]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[25]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[27]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[28]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[30]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[32]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[33]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[34]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[35]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[36]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[37]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[33]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[38]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[39]
Gefitinib	DM15F0X	Approved	Gefitinib increases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[40]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[41]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[43]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[45]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[46]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[47]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[48]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[49]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[50]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[51]
AM251	DMTAWHL	Investigative	AM251 decreases the expression of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[52]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[42]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Replication protein A 70 kDa DNA-binding subunit (RPA1).	[44]

References

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