DNA ADP-ribosylation
Definition
Target type: biologicalprocess
The covalent attachment of an ADP-ribosyl group to a residue in double-stranded DNA. [PMID:11592983, PMID:27471034, PMID:29361132, PMID:29520010]
DNA ADP-ribosylation is a post-translational modification that involves the attachment of ADP-ribose (ADPR) to proteins. This process is catalyzed by a family of enzymes known as poly(ADP-ribose) polymerases (PARPs). PARPs use nicotinamide adenine dinucleotide (NAD+) as a substrate, cleaving it to release nicotinamide and transferring the ADPR moiety to a target protein. The ADPR can be added as a single unit or as a branched polymer, creating a complex and dynamic modification.
DNA ADP-ribosylation plays a crucial role in various cellular processes, including:
* **DNA repair:** PARPs are activated by DNA damage, and their enzymatic activity is essential for the repair of single-strand breaks (SSBs) and double-strand breaks (DSBs). PARylation creates a scaffold that recruits repair factors to the damaged DNA site, facilitating the repair process.
* **Transcriptional regulation:** PARylation can modulate the activity of transcription factors, either by directly modifying them or by influencing their interactions with other proteins. This can affect the expression of genes involved in DNA repair, cell cycle control, and apoptosis.
* **Signaling pathways:** PARylation participates in various signaling pathways, such as the response to stress, inflammation, and immune activation. PARPs can act as sensors of cellular damage, activating downstream pathways to trigger appropriate cellular responses.
* **Chromatin remodeling:** PARylation can influence chromatin structure, affecting the accessibility of DNA to repair enzymes and other regulatory factors.
The process of DNA ADP-ribosylation is tightly regulated, involving a complex interplay of factors:
* **PARP activation:** Different PARPs are activated by distinct stimuli, such as DNA damage, oxidative stress, and cytokine signaling.
* **Substrate specificity:** PARPs exhibit varying substrate specificity, targeting different proteins and modifying them at specific sites.
* **Polymer chain length:** The length and branching of the ADPR polymer can influence the biological outcome of PARylation, affecting the recruitment of specific repair factors and signaling molecules.
* **PARG activity:** Poly(ADP-ribose) glycohydrolase (PARG) is an enzyme that removes ADPR from proteins, acting as a "de-PARylase" to regulate the duration and extent of PARylation.
Dysregulation of DNA ADP-ribosylation is implicated in various disease states, including cancer, neurodegenerative disorders, and inflammatory diseases. Understanding the intricate details of this modification is crucial for developing novel therapeutic strategies targeting PARP activity in these conditions.'
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Proteins (4)
| Protein | Definition | Taxonomy |
|---|---|---|
| Poly [ADP-ribose] polymerase 1 | A poly [ADP-ribose] polymerase 1 that is encoded in the genome of cow. [OMA:P18493, PRO:DNx] | Bos taurus (cattle) |
| Protein mono-ADP-ribosyltransferase PARP3 | A protein mono-ADP-ribosyltransferase PARP3 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9Y6F1] | Homo sapiens (human) |
| Poly [ADP-ribose] polymerase 2 | A poly [ADP-ribose] polymerase 2 that is encoded in the genome of human. [PRO:DNx] | Homo sapiens (human) |
| Poly [ADP-ribose] polymerase 1 | A poly [ADP-ribose] polymerase 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P09874] | Homo sapiens (human) |
Compounds (55)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| niacinamide | nicotinamide : A pyridinecarboxamide that is pyridine in which the hydrogen at position 3 is replaced by a carboxamide group. | pyridine alkaloid; pyridinecarboxamide; vitamin B3 | anti-inflammatory agent; antioxidant; cofactor; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor; EC 3.5.1.98 (histone deacetylase) inhibitor; Escherichia coli metabolite; geroprotector; human urinary metabolite; metabolite; mouse metabolite; neuroprotective agent; Saccharomyces cerevisiae metabolite; Sir2 inhibitor |
| 1,5-dihydroxyisoquinoline | 1,5-dihydroxyisoquinoline: structure in first source isoquinoline-1,5-diol : An isoquinolinol that is isoquinoline in which the hydrogens at positions 1 and 5 are replaced by hydroxy groups. | isoquinolinol | EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor |
| 3-aminobenzamide | benzamides; substituted aniline | EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor | |
| 4-amino-1,8-naphthalimide | 4-amino-1,8-naphthalimide: inhibits ADP-ribosylation; sometimes abreviated as 4-AN; | benzoisoquinoline; dicarboximide | |
| phenanthridone | phenanthridone : A member of the class of phenanthridines that is phenanthridine with an oxo substituent at position 6. A poly(ADP-ribose) polymerase (PARP) inhibitor, it has been shown to exhibit immunosuppressive activity. phenanthridone: coal tar derivative; structure given in first source | lactam; phenanthridines | EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor; immunosuppressive agent; mutagen |
| 5-aminoisoquinolinone | 5-aminoisoquinolinone: structure in first source | isoquinolines | |
| benzamide | benzamide : An aromatic amide that consists of benzene bearing a single carboxamido substituent. The parent of the class of benzamides. | benzamides | |
| pj-34 | PJ34 : A member of the class of phenanthridines that is 5,6-dihydrophenanthridine substituted at positions 2 and 6 by (N,N-dimethylglycyl)amino and oxo groups, respectively. It is a potent inhibitor of poly(ADP-ribose) polymerases PARP1 and PARP2 (IC50 of 110 nM and 86 nM, respectively) and exhibits anti-cancer, cardioprotective and neuroprotective properties. | phenanthridines; secondary carboxamide; tertiary amino compound | angiogenesis inhibitor; anti-inflammatory agent; antiatherosclerotic agent; antineoplastic agent; apoptosis inducer; cardioprotective agent; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor; neuroprotective agent |
| 3-aminobenzoic acid | 3-aminobenzoic acid : An aminobenzoic acid carrying an amino group at position 3. 3-aminobenzoic acid: RN given refers to parent cpd | aminobenzoic acid | |
| 1-hydroxyphthalazine | 1-hydroxyphthalazine: RN given refers to cpd with unspecified locants; do not confuse with cpd phthalazinol RN: 56611-65-5 | phthalazines | |
| chlorthenoxazin | chlorthenoxazin: RN given refers to parent cpd; structure | benzoxazine | |
| isocarbostyril | isoquinolinone : An isoquinoline containing one or more oxo groups. | isoquinolines | |
| flavone | flavone : The simplest member of the class of flavones that consists of 4H-chromen-4-one bearing a phenyl substituent at position 2. flavone: RN given refers to unlabeled cpd; structure given in first source | flavones | metabolite; nematicide |
| 2,4(1h,3h)-quinazolinedione | 2,4(1H,3H)-quinazolinedione: structure given in first source | ||
| 4-hydroxybenzamide | |||
| naphthalimides | Naphthalimides: Compounds with three fused rings that appear like a naphthalene fused to piperidone or like a benz(de)isoquinoline-1,3-dione (not to be confused with BENZYLISOQUINOLINES which have a methyl separating the naphthyl from the benzyl rings). Members are CYTOTOXINS. | ||
| 4-fluorobenzamide | 4-fluorobenzamide: structure in first source | ||
| 5-iodo-6-amino-1,2-benzopyrone | |||
| alantolactone | alantolactone : A sesquiterpene lactone that is 3a,5,6,7,8,8a,9,9a-octahydronaphtho[2,3-b]furan-2-one bearing two methyl substituents at positions 5 and 8a as well as a methylidene substituent at position 3. alantolactone: allergenic sesquiterpene lactone; crystalline mixture of alantolactones from group of sesquiterpenes; structure | naphthofuran; olefinic compound; sesquiterpene lactone | antineoplastic agent; apoptosis inducer; plant metabolite |
| 4-aminobenzamide | benzamides | ||
| 4-Methoxybenzamide | benzamides | ||
| 3-methoxybenzamide | |||
| 3',4'-dihydroxyflavone | 3',4'-dihydroxyflavone: inhibitors of arachidonic acid peroxidation | ||
| 3,4-dihydro-5-methyl-1(2h)-isoquinolinone | 3,4-dihydro-5-methyl-1(2H)-isoquinolinone: structure given in first source | isoquinolines | |
| 1-oxo-1,2,3,4-tetrahydroisoquinoline | 1-oxo-1,2,3,4-tetrahydroisoquinoline: structure given in first source | ||
| cyclo(alanylalanyl) | |||
| N-[4-[[[4-(4-methoxyphenyl)-4-oxanyl]methylamino]-oxomethyl]phenyl]-2-furancarboxamide | aromatic amide; furans | ||
| ha 1100 | HA 1100: intracellular calcium antagonist | ||
| apigenin | Chamomile: Common name for several daisy-like plants (MATRICARIA; TRIPLEUROSPERMUM; ANTHEMIS; CHAMAEMELUM) native to Europe and Western Asia, now naturalized in the United States and Australia. | trihydroxyflavone | antineoplastic agent; metabolite |
| luteolin | 3'-hydroxyflavonoid; tetrahydroxyflavone | angiogenesis inhibitor; anti-inflammatory agent; antineoplastic agent; apoptosis inducer; c-Jun N-terminal kinase inhibitor; EC 2.3.1.85 (fatty acid synthase) inhibitor; immunomodulator; nephroprotective agent; plant metabolite; radical scavenger; vascular endothelial growth factor receptor antagonist | |
| amentoflavone | biflavonoid; hydroxyflavone; ring assembly | angiogenesis inhibitor; antiviral agent; cathepsin B inhibitor; P450 inhibitor; plant metabolite | |
| 3',4',7-trihydroxyflavone | 3',4',7-trihydroxyflavone: from the Sudanese medicinal plant Albizia zygia; structure in first source | flavones | |
| adenosine diphosphate (hydroxymethyl)pyrrolidinediol | dihydroxypyrrolidine; purine ribonucleoside 5'-diphosphate | ||
| ag 14361 | benzimidazoles | ||
| gpi 6150 | |||
| rucaparib | AG14447: Poly(ADP-ribose) polymerase inhibitor; structure in first source | azepinoindole; caprolactams; organofluorine compound; secondary amino compound | antineoplastic agent; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor |
| 3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2h)-isoquinolinone | |||
| latonduine a | latonduine A: structure in first source | ||
| veliparib | benzimidazoles | EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor | |
| olaparib | cyclopropanes; monofluorobenzenes; N-acylpiperazine; phthalazines | antineoplastic agent; apoptosis inducer; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor | |
| niraparib | 2-[4-(piperidin-3-yl)phenyl]-2H-indazole-7-carboxamide : A member of the class of indazoles that is 2H-indazole substituted by 4-(piperidin-3-yl)phenyl and aminocarbonyl groups at positions 2 and 7, respectively. It is a potent PARP1 inhibitor with IC50 of 3.2 nM. | benzenes; indazoles; piperidines; primary carboxamide | antineoplastic agent; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor |
| niraparib | niraparib : A 2-[4-(piperidin-3-yl)phenyl]-2H-indazole-7-carboxamide that has S-configuration. It is a potent inhibitor of PARP1 and PARP2 (IC50 of 3.8 and 2.1 nM, respectively) and approved as a first-line maintenance treatment for women with advanced ovarian cancer after responding to platinum-based chemotherapy. niraparib: structure in first source | 2-[4-(piperidin-3-yl)phenyl]-2H-indazole-7-carboxamide | antineoplastic agent; apoptosis inducer; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor; radiosensitizing agent |
| cep 26401 | pyridazines; ring assembly | ||
| iwr-1 endo | IWR-1-endo : A dicarboximide having an endo bridged phthalimide structure, substituted at nitrogen by a 4-(quinolin-8-ylcarbamoyl)benzoyl group. | benzamides; bridged compound; dicarboximide; quinolines | axin stabilizer; Wnt signalling inhibitor |
| nms-p118 | NMS-P118: a PARP-1 inhibitor; structure in first source | ||
| g007-lk | G007-LK: potent and specific small-molecule tankyrase inhibitor; structure in first source | ||
| nu 1025 | NU 1064: structure in first source | phenols; quinazolines | EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor |
| 2-methyl-4(3h)-quinazolinone | 2-methyl-4(3H)-quinazolinone: from Bacillus cereus; structure given in first source | ||
| 4-hydroxyquinazoline | 4-oxo-3,4-dihydroquinazoline: structure in first source | quinazolines | |
| 1,4-Dihydrothieno[3,2-d]pyrimidin-4-one | organic heterobicyclic compound; organonitrogen heterocyclic compound; organosulfur heterocyclic compound | ||
| xav939 | XAV939 : A thiopyranopyrimidine in which a 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine skeleton is substituted at C-4 by a hydroxy group and at C-2 by a para-(trifluoromethyl)phenyl group. XAV939: selectively inhibits beta-catenin-mediated transcription; structure in first source | (trifluoromethyl)benzenes; thiopyranopyrimidine | tankyrase inhibitor |
| 2-(4-methoxyphenyl)-1H-quinazolin-4-one | quinazolines | ||
| bmn 673 | talazoparib: inhibits both PARP1 and PARP2; structure in first source | ||
| me0328 | ME0328: inhibits ARTD3; structure in first source | ||
| nvp-tnks656 |