double-strand break repair via classical nonhomologous end joining

Definition

Target type: biologicalprocess

An instance of double-strand break repair via nonhomologous end joining that requires a number of factors important for V(D)J recombination, including the KU70/80 heterodimer (KU), XRCC4, ligase IV, and DNA-PKcs in mammals. It does not produce translocations (as opposed to the alternative nonhomologous end joining). [GOC:rph, PMID:18584027]

Classical non-homologous end joining (c-NHEJ) is a primary DNA double-strand break (DSB) repair pathway that operates throughout the cell cycle. It is characterized by its direct ligation of broken DNA ends without the need for a homologous template, making it an error-prone process. Here's a detailed description of the c-NHEJ process:

1. **DSB Recognition and End Processing:** The DNA ends are recognized by the Ku70/80 heterodimer, which binds to the DNA ends with high affinity, protecting them from degradation and promoting the recruitment of other repair factors. The DNA ends may be resected to a limited extent by nucleases, removing any 5'-phosphate groups and generating 3'-hydroxyl groups.

2. **End Bridging and Synapsis:** The Ku70/80 complex acts as a scaffold to recruit the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), forming a complex known as the DNA-PK holoenzyme. DNA-PKcs is a large serine/threonine protein kinase that autophosphorylates and phosphorylates other repair factors, leading to conformational changes that facilitate end bridging and synapsis. The DNA ends are brought together, forming a synaptic complex.

3. **Gap Filling and Ligation:** The DNA ends are then processed by the Artemis nuclease, which removes any remaining overhangs and generates blunt ends. A small gap may remain between the blunt ends, which is filled in by DNA polymerase. The DNA ends are finally ligated by DNA ligase IV in complex with its cofactor XRCC4, resulting in the restoration of the DNA backbone.

4. **Quality Control and Error Correction:** While c-NHEJ is efficient, it can introduce mutations due to the lack of a template. Several mechanisms contribute to quality control, including the 3'-5' exonuclease activity of DNA polymerase and the ability of DNA-PKcs to sense mismatched ends. However, these mechanisms are not perfect, and c-NHEJ can result in deletions, insertions, and translocations, contributing to genomic instability.

In summary, c-NHEJ is a fast and efficient DSB repair pathway that operates throughout the cell cycle. It relies on direct ligation of DNA ends, which makes it susceptible to error. However, its role in maintaining genomic integrity is essential, and it is particularly important in non-dividing cells where homologous recombination is not available.'
"

Proteins (1)

Compounds (2)