negative regulation of double-strand break repair via nonhomologous end joining
Definition
Target type: biologicalprocess
Any process that stops, prevents or reduces the frequency, rate or extent of double-strand break repair via nonhomologous end joining. [GOC:obol]
Negative regulation of double-strand break repair via nonhomologous end joining (NHEJ) is a complex process that ensures accurate DNA repair while preventing inappropriate joining events. It involves several key steps:
1. **DNA Damage Recognition:** Following a double-strand break, specialized proteins like Ku70/Ku80 heterodimer bind to the broken DNA ends, protecting them from degradation and serving as a platform for the recruitment of other repair factors.
2. **End Processing:** The broken ends often require processing to facilitate joining. This step involves trimming back the ends, removing any overhangs, and creating compatible 5' phosphate and 3' hydroxyl groups for ligation.
3. **Ligase Recruitment:** Once the ends are prepared, the DNA ligase IV-XRCC4 complex is recruited, catalyzing the joining of the two DNA ends.
4. **Regulation of NHEJ:** Several mechanisms regulate NHEJ to ensure fidelity and prevent aberrant joining events. These include:
* **Phosphorylation of key proteins:** Kinases like ATM and DNA-PKcs phosphorylate NHEJ proteins, influencing their activity and localization.
* **Ubiquitination of repair factors:** Ubiquitin ligases target NHEJ proteins, affecting their stability and interactions.
* **Competition with homologous recombination (HR):** HR is an alternative repair pathway that is generally more accurate than NHEJ, especially for larger breaks. When HR is active, it can suppress NHEJ.
* **Negative regulation by specific proteins:** Certain proteins act as inhibitors of NHEJ. For example, 53BP1 blocks the resection of DNA ends, preventing the use of HR and promoting NHEJ.
5. **Final Ligation:** The DNA ligase IV-XRCC4 complex seals the DNA ends, restoring the integrity of the genome.
**Negative regulation of NHEJ** is essential for maintaining genomic stability. Inhibiting NHEJ can lead to increased chromosomal instability, mutations, and cancer development. Conversely, hyperactive NHEJ can result in aberrant DNA repair, leading to deletions, insertions, and translocations.
In summary, negative regulation of NHEJ is a multi-faceted process involving various proteins and mechanisms. These mechanisms ensure precise DNA repair while preventing the detrimental effects of excessive or inappropriate NHEJ activity.'
"
Proteins (1)
| Protein | Definition | Taxonomy |
|---|---|---|
| Heat shock factor protein 1 | A heat shock factor protein 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q00613] | Homo sapiens (human) |
Compounds (11)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| zm 336372 | N-(5-(3-dimethylaminobenzamido)-2-methylphenyl)-4-hydroxybenzamide: an inhibitor of c-Raf; activates Raf-1; structure in first source | benzamides | |
| celastrol | monocarboxylic acid; pentacyclic triterpenoid | anti-inflammatory drug; antineoplastic agent; antioxidant; EC 5.99.1.3 [DNA topoisomerase (ATP-hydrolysing)] inhibitor; Hsp90 inhibitor; metabolite | |
| quercetin | 7-hydroxyflavonol; pentahydroxyflavone | antibacterial agent; antineoplastic agent; antioxidant; Aurora kinase inhibitor; chelator; EC 1.10.99.2 [ribosyldihydronicotinamide dehydrogenase (quinone)] inhibitor; geroprotector; phytoestrogen; plant metabolite; protein kinase inhibitor; radical scavenger | |
| chir-265 | aromatic ether | ||
| az-628 | AZ-628: a multikinase inhibitor; structure in first source | benzamides | |
| GDC-0879 | indanes; ketoxime; primary alcohol; pyrazoles; pyridines | antineoplastic agent; B-Raf inhibitor | |
| plx4032 | aromatic ketone; difluorobenzene; monochlorobenzenes; pyrrolopyridine; sulfonamide | antineoplastic agent; B-Raf inhibitor | |
| dabrafenib | 1,3-thiazoles; aminopyrimidine; organofluorine compound; sulfonamide | anticoronaviral agent; antineoplastic agent; B-Raf inhibitor | |
| tak-632 | TAK-632 : A member of the class of benzothiazoles that is 1,3-benzothiazole substituted by (cyclopropanecarbonyl)amino, 4-fluoro-3-{2-[3-(trifluoromethyl)phenyl]acetamido}phenoxy, and cyano groups at positions 2, 6 and 7, respectively. It is a potent pan-RAF inhibitor with IC50 of 1.4, 2.4 and 8.3 nM for CRAF, BRAF(V600E), BRAF(WT), respectively. | (trifluoromethyl)benzenes; aromatic ether; benzothiazoles; cyclopropylcarboxamide; monofluorobenzenes; nitrile; secondary carboxamide | antineoplastic agent; apoptosis inducer; B-Raf inhibitor; EC 2.7.11.26 (tau-protein kinase) inhibitor; necroptosis inhibitor |
| dinaciclib | pyrazolopyrimidine | ||
| n2-(1h-indazole-5-yl)-n6-methyl-3-nitropyridine-2,6-diamine | KRIBB11 : A member of the class of indazoles that is 1H-indazole substituted by a [6-(methylamino)-3-nitropyridin-2-yl]amino group at position 5. It is an inhibitor of heat shock factor 1 (IC50 = 1.2muM) and suppresses tumour growth in mouse xenograft models. N2-(1H-indazole-5-yl)-N6-methyl-3-nitropyridine-2,6-diamine: a heat shock factor 1 antagonist; structure in first source |