negative regulation of DNA-templated DNA replication
Definition
Target type: biologicalprocess
Any process that stops, prevents, or reduces the frequency, rate or extent of DNA-dependent DNA replication. [GOC:mah]
Negative regulation of DNA-templated DNA replication is a critical process that ensures precise and timely duplication of the genome. It involves a complex interplay of proteins and regulatory mechanisms that act to suppress or slow down DNA replication, preventing uncontrolled replication and maintaining genomic integrity.
**Key players in negative regulation:**
* **Replication licensing factors:** These proteins, such as the origin recognition complex (ORC) and Cdc6, bind to origins of replication in the G1 phase of the cell cycle, marking them as potential sites for DNA replication initiation.
* **DNA replication inhibitors:** These proteins, such as geminin, inhibit the re-licensing of origins, ensuring that each origin is only replicated once per cell cycle.
* **Checkpoint kinases:** These enzymes, like ATM and ATR, sense DNA damage or replication stress and activate signaling pathways that arrest the cell cycle, allowing time for repair.
* **DNA damage response (DDR) proteins:** These proteins, such as p53, induce cell cycle arrest or apoptosis in response to irreparable DNA damage.
**Steps involved in negative regulation:**
1. **Origin licensing:** In G1 phase, licensing factors bind to origins, making them competent for replication.
2. **Replication initiation:** In S phase, DNA polymerase and other proteins assemble at licensed origins, initiating DNA replication.
3. **Origin inactivation:** Once replication has started, the licensing factors are removed from the origin, preventing further replication initiation.
4. **Checkpoint activation:** If DNA damage or replication stress is encountered, checkpoint kinases are activated.
5. **Cell cycle arrest:** Activated checkpoint kinases halt the cell cycle, allowing time for DNA repair.
6. **Re-licensing inhibition:** Geminin binds to licensing factors, preventing them from re-binding to origins, ensuring that each origin is replicated only once.
**Consequences of deregulation:**
* **Genomic instability:** Uncontrolled replication can lead to mutations, deletions, and amplifications, contributing to cancer development.
* **Cell cycle dysregulation:** Aberrant regulation can cause uncontrolled cell proliferation and tumor growth.
**Clinical relevance:**
* **Cancer therapy:** Targeting components of the negative regulation pathway is a promising strategy for cancer treatment, as it can induce cell cycle arrest and apoptosis in cancer cells.
* **Aging and disease:** Dysregulation of DNA replication control contributes to age-related decline and diseases like neurodegenerative disorders.'
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Proteins (1)
| Protein | Definition | Taxonomy |
|---|---|---|
| DNA gyrase subunit A | A DNA gyrase subunit A that is encoded in the genome of Escherichia coli K-12. [PRO:DNx, UniProtKB:P0AES4] | Escherichia coli K-12 |
Compounds (18)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| ciprofloxacin | ciprofloxacin : A quinolone that is quinolin-4(1H)-one bearing cyclopropyl, carboxylic acid, fluoro and piperazin-1-yl substituents at positions 1, 3, 6 and 7, respectively. Ciprofloxacin: A broad-spectrum antimicrobial carboxyfluoroquinoline. | aminoquinoline; cyclopropanes; fluoroquinolone antibiotic; N-arylpiperazine; quinolinemonocarboxylic acid; quinolone; quinolone antibiotic; zwitterion | antibacterial drug; antiinfective agent; antimicrobial agent; DNA synthesis inhibitor; EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor; environmental contaminant; topoisomerase IV inhibitor; xenobiotic |
| enoxacin | enoxacin : A 1,8-naphthyridine derivative that is 1,4-dihydro-1,8-naphthyridine with an ethyl group at the 1 position, a carboxy group at the 3-position, an oxo sustituent at the 4-position, a fluoro substituent at the 5-position and a piperazin-1-yl group at the 7 position. An antibacterial, it is used in the treatment of urinary-tract infections and gonorrhoea. Enoxacin: A broad-spectrum 6-fluoronaphthyridinone antibacterial agent that is structurally related to NALIDIXIC ACID. | 1,8-naphthyridine derivative; amino acid; fluoroquinolone antibiotic; monocarboxylic acid; N-arylpiperazine; quinolone antibiotic | antibacterial drug; DNA synthesis inhibitor |
| isoniazid | Hydra: A genus of freshwater polyps in the family Hydridae, order Hydroida, class HYDROZOA. They are of special interest because of their complex organization and because their adult organization corresponds roughly to the gastrula of higher animals. hydrazide : Compounds derived from oxoacids RkE(=O)l(OH)m (l =/= 0) by replacing -OH by -NRNR2 (R groups are commonly H). (IUPAC). | carbohydrazide | antitubercular agent; drug allergen |
| nalidixic acid | 1,8-naphthyridine derivative; monocarboxylic acid; quinolone antibiotic | antibacterial drug; antimicrobial agent; DNA synthesis inhibitor | |
| norfloxacin | norfloxacin : A quinolinemonocarboxylic acid with broad-spectrum antibacterial activity against most gram-negative and gram-positive bacteria. Norfloxacin is bactericidal and its mode of action depends on blocking of bacterial DNA replication by binding itself to an enzyme called DNA gyrase. Norfloxacin: A synthetic fluoroquinolone (FLUOROQUINOLONES) with broad-spectrum antibacterial activity against most gram-negative and gram-positive bacteria. Norfloxacin inhibits bacterial DNA GYRASE. | fluoroquinolone antibiotic; N-arylpiperazine; quinolinemonocarboxylic acid; quinolone; quinolone antibiotic | antibacterial drug; DNA synthesis inhibitor; environmental contaminant; xenobiotic |
| ofloxacin | 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid : An oxazinoquinoline that is 2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one substituted by methyl, carboxy, fluoro, and 4-methylpiperazin-1-yl groups at positions 3, 6, 9, and 10, respectively. ofloxacin : A racemate comprising equimolar amounts of levofloxacin and dextrofloxacin. It is a synthetic fluoroquinolone antibacterial agent which inhibits the supercoiling activity of bacterial DNA gyrase, halting DNA replication. Ofloxacin: A synthetic fluoroquinolone antibacterial agent that inhibits the supercoiling activity of bacterial DNA GYRASE, halting DNA REPLICATION. | 3-oxo monocarboxylic acid; N-arylpiperazine; N-methylpiperazine; organofluorine compound; oxazinoquinoline | |
| gatifloxacin | gatifloxacin : A monocarboxylic acid that is 4-oxo-1,4-dihydroquinoline-3-carboxylic acid which is substituted on the nitrogen by a cyclopropyl group and at positions 6, 7, and 8 by fluoro, 3-methylpiperazin-1-yl, and methoxy groups, respectively. Gatifloxacin is an antibiotic of the fourth-generation fluoroquinolone family, that like other members of that family, inhibits the bacterial topoisomerase type-II enzymes. Gatifloxacin: A fluoroquinolone antibacterial agent and DNA TOPOISOMERASE II inhibitor that is used as an ophthalmic solution for the treatment of BACTERIAL CONJUNCTIVITIS. | N-arylpiperazine; organofluorine compound; quinolinemonocarboxylic acid; quinolone; quinolone antibiotic | antiinfective agent; antimicrobial agent; EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor |
| triclosan | aromatic ether; dichlorobenzene; monochlorobenzenes; phenols | antibacterial agent; antimalarial; drug allergen; EC 1.3.1.9 [enoyl-[acyl-carrier-protein] reductase (NADH)] inhibitor; EC 1.5.1.3 (dihydrofolate reductase) inhibitor; fungicide; persistent organic pollutant; xenobiotic | |
| 4-cumylphenol | diarylmethane | ||
| 4-phenoxyphenol | phenoxyphenol | ||
| bis(4-oxyphenyl)sulfide | 4,4'-thiodiphenol: structure in first source | phenols | |
| moxifloxacin | moxifloxacin : A quinolone that consists of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid bearing a cyclopropyl substituent at position 1, a fluoro substitiuent at position 6, a (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl group at position 7 and a methoxy substituent at position 8. A member of the fluoroquinolone class of antibacterial agents. Moxifloxacin: A fluoroquinolone that acts as an inhibitor of DNA TOPOISOMERASE II and is used as a broad-spectrum antibacterial agent. | aromatic ether; cyclopropanes; fluoroquinolone antibiotic; pyrrolidinopiperidine; quinolinemonocarboxylic acid; quinolone; quinolone antibiotic | antibacterial drug |
| linezolid | acetamides; morpholines; organofluorine compound; oxazolidinone | antibacterial drug; protein synthesis inhibitor | |
| gemifloxacin | gemifloxacin : A 1,4-dihydro-1,8-naphthyridine with a carboxy group at the 3-position, an oxo sustituent at the 4-position, a fluoro substituent at the 5-position and a substituted pyrrolin-1-yl group at the 7-position. Gemifloxacin: A naphthyridine and fluoroquinolone derivative antibacterial agent and DNA TOPOISOMERASE II inhibitor that is used for the treatment of community-acquired pneumonia and acute bacterial infections associated with chronic bronchitis. | 1,8-naphthyridine derivative; fluoroquinolone antibiotic; monocarboxylic acid; quinolone antibiotic | antibacterial drug; antimicrobial agent; topoisomerase IV inhibitor |
| pd 0305970 | |||
| gsk299423 | GSK299423: structure in first source | ||
| novobiocin | novobiocin : A coumarin-derived antibiotic obtained from Streptomyces niveus. Novobiocin: An antibiotic compound derived from Streptomyces niveus. It has a chemical structure similar to coumarin. Novobiocin binds to DNA gyrase, and blocks adenosine triphosphatase (ATPase) activity. (From Reynolds, Martindale The Extra Pharmacopoeia, 30th ed, p189) | carbamate ester; ether; hexoside; hydroxycoumarin; monocarboxylic acid amide; monosaccharide derivative; phenols | antibacterial agent; antimicrobial agent; EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor; Escherichia coli metabolite; hepatoprotective agent |
| clorobiocin | clorobiocin: chlorine-containing antibiotic related to novobiocin |