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Non-homologous end joining
Non-homologous end joining (NHEJ) is also one of the major pathways in DSB repair. The basic concept of NHEJ involves three steps: first, the ends of DSB are captured by a group of enzymes; second, the enzymes forms a bridge which connects the DSB ends together; third, the DNA is religated together. To initiate NHEJ, the protein complex Ku70/80 binds to the damaged ends of both broken DNA strands. This forms a preliminary scaffold which allows the recruitment of various NHEJ factors, such as DNA-dependent protein kinase catalytic subunit (DNA-PKcs), X-ray cross complementing protein 4 (XRCC4), DNA Ligase IV, to form a bridge and bring both ends of the broken DNA strands together. The step is then followed by the processing of any non-ligatable DNA termini by proteins such as Artemis, PNKP, APLF and Ku, before the subsquent ligation of the bridged DNA strands by DNA Ligase IV and XRCC4.

DNA damage response
DNA damage response (DDR) is the overarching mechanism which mediates the cell's detection and response to DNA damage. This includes the process of detecting DSBs within the cell, and the subsequent triggering and regulation of DSB repair pathways. Upstream detections of DNA damage via DDR will lead to the activation of downstream responses such as senescence, cell apoptosis, halting transcription and activating DNA repair mechanisms. Proteins such as the proteins ATM, ATR and DNA-dependent protein kinase (DNA-PK) are vital for the process of detection of DSB in DDR, and are recruited to DNA damage sites when DSB occurs. In particular, ATM has been identified as the protein kinase in charge of the global meditation of cellular responses to DSBs, which includes various DSB repair pathways. Following the recruitment of the aforementioned proteins to DNA damage sites, they will in turn trigger cellular responses and repair pathways to mitigate and repair the damage caused. In short, these vital upstream proteins and downstream repair pathways altogether forms the DDR, which plays a vital role in the regulation of DSB repair pathways.

Double strand break repair pathway choice
As there are many of ways which DSBs could occur, cells have evolved a multitude of pathways in response to them. Specific pathways are favoured for their ability to repair DSBs in certain situations. For instance, frank DSBs, which are DSBs induced by substances like as ionizing radiation, and nucleases, can be repaired by both HR and NHEJ. On the other hand, DSBs due to replication fork collapse mainly favours HR.

It is said that the favoured pathway in a particular situations is also largely dependent on the species of the cell, the cell type, and cell cycle phases; and are all modulated and triggered by different upstream regulatory proteins. As compared to higher eukaryotes, yeast cells have adopted HR as the main repair pathway for DSBs. Imprecise NHEJ, the primary pathway for NHEJ to repair "dirty" ends due to IR, was found to be inefficent at repairing DSBs in yeast cells. In the experiment, researchers inhibited HR pathways, which forced yeast cells to adopt NHEJ as the main repair pathway. This has resulted in a dismal survival rate of yeast cells due to their inability to repair DSB via imprecise NHEJ shows the inefficient of NHEJ in yeast cells. It was hypothesized that this inefficient as compared to mammalian cells is due to the lack of three vital NHEJ proteins, including DNA-PKcs, BRCA1, and Artemis. On the contrary, higher eukaryotes has a much higher frequency and efficiency at adopting NHEJ pathways. Researchers believe that it is due to their larger genome size, as it means that more NHEJ related proteins are encoded for NHEJ repair pathways; and a larger genome implies a greater challenge to find a homologous template for HR.

HR and NHEJ pathways are favoured in various phases of cell cycles for a multitude of factors. As S and G2 phases of the cell cycle generate more chromatids, the increased availability of template access for HR results in the up-regulation of the pathway. This up-regulation is further increased due to the activation of CDK1 and the increase of RAD51 and RAD52 levels during G1 phase. Despite this, NHEJ not is inactive during the HR up-regulation. In fact, NHEJ was shown to be active throughout all stages of the cell cycle, and is favoured in G1 phase during low resection action intervals. This suggests the competition between HR and NHEJ for DSB repair in cells. It should be noted, however, that there is a shift of favour from NHEJ to HR as cell cycle progresses from G1 to S/G2 phases in eukaryotic cells.

Microhomology-mediated end joining
Microhomology-mediated end joining (MMEJ), also known as alt-non-homologous end joining, is a pathway to repair DSBs within cells. The process of MMEJ can be summarised in five steps: the 5' to 3' cutting of DNA ends, annealing of microhomology, removing heterologous flaps, and ligation and synthesis of gap filling DNA. It was found that the selection between NHEJ and MMEJ is mainly dependent on Ku levels and the concurrent cell cycle.