Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPE49OE)

• DOT Name: Telomere-associated protein RIF1 (RIF1)
• Synonyms: Rap1-interacting factor 1 homolog
• Gene Name: RIF1
• Related Disease:
  Colorectal carcinoma
  Gastric cancer
  Nemaline myopathy 2
  Stomach cancer
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Epithelial ovarian cancer
  Fibrosarcoma
  Neoplasm
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Bloom syndrome
  Nemaline myopathy
• UniProt ID: RIF1_HUMAN
• Pfam ID: PF12231
• Sequence:
  MTARGQSPLAPLLETLEDPSASHGGQTDAYLTLTSRMTGEEGKEVITEIEKKLPRLYKVL
  KTHISSQNSELSSAALQALGFCLYNPKITSELSEANALELLSKLNDTIKNSDKNVRTRAL
  WVISKQTFPSEVVGKMVSSIIDSLEILFNKGETHSAVVDFEALNVIVRLIEQAPIQMGEE
  AVRWAKLVIPLVVHSAQKVHLRGATALEMGMPLLLQKQQEIASITEQLMTTKLISELQKL
  FMSKNETYVLKLWPLFVKLLGRTLHRSGSFINSLLQLEELGFRSGAPMIKKIAFIAWKSL
  IDNFALNPDILCSAKRLKLLMQPLSSIHVRTETLALTKLEVWWYLLMRLGPHLPANFEQV
  CVPLIQSTISIDSNASPQGNSCHVATSPGLNPMTPVHKGASSPYGAPGTPRMNLSSNLGG
  MATIPSIQLLGLEMLLHFLLGPEALSFAKQNKLVLSLEPLEHPLISSPSFFSKHANTLIT
  AVHDSFVAVGKDAPDVVVSAIWKELISLVKSVTESGNKKEKPGSEVLTLLLKSLESIVKS
  EVFPVSKTLVLMEITIKGLPQKVLGSPAYQVANMDILNGTPALFLIQLIFNNFLECGVSD
  ERFFLSLESLVGCVLSGPTSPLAFSDSVLNVINQNAKQLENKEHLWKMWSVIVTPLTELI
  NQTNEVNQGDALEHNFSAIYGALTLPVNHIFSEQRFPVATMKTLLRTWSELYRAFARCAA
  LVATAEENLCCEELSSKIMSSLEDEGFSNLLFVDRIIYIITVMVDCIDFSPYNIKYQPKV
  KSPQRPSDWSKKKNEPLGKLTSLFKLIVKVIYSFHTLSFKEAHSDTLFTIGNSITGIISS
  VLGHISLPSMIRKIFATLTRPLALFYENSKLDEVPKVYSCLNNKLEKLLGEIIACLQFSY
  TGTYDSELLEQLSPLLCIIFLHKNKQIRKQSAQFWNATFAKVMMLVYPEELKPVLTQAKQ
  KFLLLLPGLETVEMMEESSGPYSDGTENSQLNVKISGMERKSNGKRDSFLAQTKNKKENM
  KPAAKLKLESSSLKVKGEILLEEEKSTDFVFIPPEGKDAKERILTDHQKEVLKTKRCDIP
  AMYNNLDVSQDTLFTQYSQEEPMEIPTLTRKPKEDSKMMITEEQMDSDIVIPQDVTEDCG
  MAEHLEKSSLSNNECGSLDKTSPEMSNSNNDERKKALISSRKTSTECASSTENSFVVSSS
  SVSNTTVAGTPPYPTSRRQTFITLEKFDGSENRPFSPSPLNNISSTVTVKNNQETMIKTD
  FLPKAKQREGTFSKSDSEKIVNGTKRSSRRAGKAEQTGNKRSKPLMRSEPEKNTEESVEG
  IVVLENNPPGLLNQTECVSDNQVHLSESTMEHDNTKLKAATVENAVLLETNTVEEKNVEI
  NLESKENTPPVVISADQMVNEDSQVQITPNQKTLRRSSRRRSEVVESTTESQDKENSHQK
  KERRKEEEKPLQKSPLHIKDDVLPKQKLIAEQTLQENLIEKGSNLHEKTLGETSANAETE
  QNKKKADPENIKSEGDGTQDIVDKSSEKLVRGRTRYQTRRASQGLLSSIENSESDSSEAK
  EEGSRKKRSGKWKNKSNESVDIQDQEEKVVKQECIKAENQSHDYKATSEEDVSIKSPICE
  KQDESNTVICQDSTVTSDLLQVPDDLPNVCEEKNETSKYAEYSFTSLPVPESNLRTRNAI
  KRLHKRDSFDNCSLGESSKIGISDISSLSEKTFQTLECQHKRSRRVRRSKGCDCCGEKSQ
  PQEKSLIGLKNTENNDVEISETKKADVQAPVSPSETSQANPYSEGQFLDEHHSVNFHLGL
  KEDNDTINDSLIVSETKSKENTMQESLPSGIVNFREEICDMDSSEAMSLESQESPNENFK
  TVGPCLGDSKNVSQESLETKEEKPEETPKMELSLENVTVEGNACKVTESNLEKAKTMELN
  VGNEASFHGQERTKTGISEEAAIEENKRNDDSEADTAKLNAKEVATEEFNSDISLSDNTT
  PVKLNAQTEISEQTAAGELDGGNDVSDLHSSEETNTKMKNNEEMMIGEAMAETGHDGETE
  NEGITTKTSKPDEAETNMLTAEMDNFVCDTVEMSTEEGIIDANKTETNTEYSKSEEKLDN
  NQMVMESDILQEDHHTSQKVEEPSQCLASGTAISELIIEDNNASPQKLRELDPSLVSAND
  SPSGMQTRCVWSPLASPSTSILKRGLKRSQEDEISSPVNKVRRVSFADPIYQAGLADDID
  RRCSIVRSHSSNSSPIGKSVKTSPTTQSKHNTTSAKGFLSPGSRSPKFKSSKKCLISEMA
  KESIPCPTESVYPPLVNCVAPVDIILPQITSNMWARGLGQLIRAKNIKTIGDLSTLTASE
  IKTLPIRSPKVSNVKKALRIYHEQQVKTRGLEEIPVFDISEKTVNGIENKSLSPDEERLV
  SDIIDPVALEIPLSKNLLAQISALALQLDSEDLHNYSGSQLFEMHEKLSCMANSVIKNLQ
  SRWRSPSHENSI
• Function: Key regulator of TP53BP1 that plays a key role in the repair of double-strand DNA breaks (DSBs) in response to DNA damage: acts by promoting non-homologous end joining (NHEJ)-mediated repair of DSBs. In response to DNA damage, interacts with ATM-phosphorylated TP53BP1. Interaction with TP53BP1 leads to dissociate the interaction between NUDT16L1/TIRR and TP53BP1, thereby unmasking the tandem Tudor-like domain of TP53BP1 and allowing recruitment to DNA DSBs. Once recruited to DSBs, RIF1 and TP53BP1 act by promoting NHEJ-mediated repair of DSBs. In the same time, RIF1 and TP53BP1 specifically counteract the function of BRCA1 by blocking DSBs resection via homologous recombination (HR) during G1 phase. Also required for immunoglobulin class-switch recombination (CSR) during antibody genesis, a process that involves the generation of DNA DSBs. Promotes NHEJ of dysfunctional telomeres.
• Tissue Specificity: Highly expressed in testis.
• KEGG Pathway: Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway: Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Genetic Variation	[1]
Gastric cancer	DISXGOUK	Definitive	Genetic Variation	[1]
Nemaline myopathy 2	DIS53UZ2	Definitive	CausalMutation	[2]
Stomach cancer	DISKIJSX	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Cervical cancer	DISFSHPF	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[3]
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[7]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[7]
Bloom syndrome	DISKXQ7J	moderate	Biomarker	[8]
Nemaline myopathy	DIS5IYLY	Limited	Genetic Variation	[9]

16 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 Telomere-associated protein RIF1 (RIF1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Telomere-associated protein RIF1 (RIF1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Telomere-associated protein RIF1 (RIF1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Telomere-associated protein RIF1 (RIF1).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Telomere-associated protein RIF1 (RIF1).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Telomere-associated protein RIF1 (RIF1).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Telomere-associated protein RIF1 (RIF1).	[16]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Telomere-associated protein RIF1 (RIF1).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Telomere-associated protein RIF1 (RIF1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Telomere-associated protein RIF1 (RIF1).	[19]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Telomere-associated protein RIF1 (RIF1).	[11]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Telomere-associated protein RIF1 (RIF1).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Telomere-associated protein RIF1 (RIF1).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Telomere-associated protein RIF1 (RIF1).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Telomere-associated protein RIF1 (RIF1).	[26]
biochanin A	DM0HPWY	Investigative	biochanin A decreases the expression of Telomere-associated protein RIF1 (RIF1).	[27]

4 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 increases the methylation of Telomere-associated protein RIF1 (RIF1).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Telomere-associated protein RIF1 (RIF1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Telomere-associated protein RIF1 (RIF1).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Telomere-associated protein RIF1 (RIF1).	[21]

References

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• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] 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.
• [22] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [23] 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.
• [24] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
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• [27] Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts. Prostate. 2002 Aug 1;52(3):201-12.