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.'
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Proteins (1)

Compounds (11)