Fixing Double-strand Breaks

When both strands of DNA are damaged, there is no intact template left for accurate repair but if left unrepaired, this scenario can lead to cell death. 

There are two mechanisms to repair double-strand breaks. The first type, non-homologous end joining, permits joining of ends even if there is no sequence similarity between them - and takes place before DNA duplication when the DNA needs quick repair. 

In mammalian cells, this is carried out by the DNA end-binding heterodimeric protein Ku which forms a complex with the catalytic subunits of DNA-dependent protein kinase. 

This complex holds the broken chromosome ends in place while a DNA polymerase inserts nucleotides to bridge the gap between these ends. Next, DNA ligase IV forms a complex with its cofactor XRCC and another protein called XLF, and rejoins and seals these ends.

Quick fixes like these can lead to mutations at the repair site, or genomic rearrangements including deletions, translocations of genetic material, and fusions which may result in chromosomes with two centromeres, or lacking centromeres altogether. 

Mutations are widespread, and human somatic cells can tolerate as many as 2000 of these. Genomic rearrangements, on the other hand, are rare - but can be found in cancerous cells. 

Most DNA double-strand breaks lead to single-stranded overhangs and the second repair type, homologous recombination, fixes these breaks. This form of recombination is much more accurate than non-homologous end joining and requires DNA from a sister chromatid as a template– so it typically occurs after gene duplication during cell division.