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non-homologous end joining

Tuesday 7 March 2006

Non-Homologous End-Joining (NHEJ) rejoins the two ends of the break in absence of a template sequence. However there is often DNA sequence loss during this process and so this repair can be mutagenic.

NHEJ can occur at all stages of the cell cycle but in mammalian cells is the main repair mechanism until DNA replication makes it possible for recombinational repair to use the sister chromatid as a template.

Since the vast majority of the genome in humans and other multicellular organisms is made up of DNA that contains no genes, the so-called "junk DNA", mutagenic NHEJ is likely to be less harmful than template-assisted repair would be in presence of multiple template sequences, since in the latter case undesirable chromosomal rearrangements are generated.

To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate.

DNA ligase

DNA ligase is an enzyme that joins broken nucleotides together by catalyzing the formation of an internucleotide ester bond between the phosphate backbone and the deoxyribose nucleotides.

DNA Ligase IV is a specialized DNA Ligase that forms a complex with the cofactor XRCC4. In NHEJ, DNA Ligase IV directly joins the two ends.

Mutations

NHEJ can also introduce mutations during repair. Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms translocations.

NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination.

There are "backup" NHEJ pathways in higher eukaryotes.

V(D)J recombination

Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during V(D)J recombination, the process that generates diversity in B-cell and T-cell receptors in the vertebrate immune system.

The enzymatic machinery used for NHEJ is utilized in B-cells to rejoin breaks created by the RAG proteins during VDJ recombination.

See also

- DNA repair
- DNA double strand breaks
- DNA double-strand break repair
- carcinogenesis/tumorigenesis
- oncogenetics

Open References

- DNA double strand break repair via non-homologous end-joining. Davis AJ, Chen DJ. Transl Cancer Res. 2013 Jun;2(3):130-143. PMID: 24000320 [Free]