What is alt NHEJ?

Alternative NHEJ (alt-NHEJ) refers to more recently described mechanism(s) that repair DSBs in less-efficient backup reactions. There is great interest in defining alt-NHEJ more precisely, including its regulation relative to c-NHEJ, in light of evidence that alt-NHEJ can execute chromosome rearrangements.

What are Microhomologous sequences?

Microhomology-mediated end joining (MMEJ) is a mutagenic double-strand break (DSB) repair mechanism that uses 1-16 nt of homology flanking the initiating DSB to align the ends for repair. MMEJ is associated with deletions and insertions that mark the original break site, as well as chromosome translocations.

What are DNA repair pathways?

DNA repair pathways are triggered to maintain genetic stability and integrity when mammalian cells are exposed to endogenous or exogenous DNA-damaging agents. The deregulation of DNA repair pathways is associated with the initiation and progression of cancer.

What is TMEJ?

A specialized form of MMEJ, called polymerase theta-mediated end-joining (TMEJ), is able to repair breaks using ≥1 bp of homology. Following annealing, any overhanging bases (flaps) are removed by nucleases such as Fen1 and gaps are filled in by DNA polymerase theta.

What causes double strand breaks?

The genome of a cell is continuously damaged, which is inevitable because DNA damage often arises as a result of normal cellular processes. The result is double-strand breaks (DSBs) in the chromosome. A DSB can also be caused by environmental exposure to irradiation, other chemical agents, or ultraviolet light (UV).

What happens in non-homologous end joining?

Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. When the overhangs are perfectly compatible, NHEJ usually repairs the break accurately. Imprecise repair leading to loss of nucleotides can also occur, but is much more common when the overhangs are not compatible.

Is NHEJ more accurate than HDR?

At its core, NHEJ-break ends can be ligated without a homologous template, whereas HDR-breaks requires a template to guide repair. NHEJ is a very efficient repair mechanism that is most active in the cell. HDR-edited DNA is much more desirable to ensure controlled modifications.

Which is an alternative pathway to NHEJ and alt-NHEJ?

Alt-NHEJ is an alternative, backup pathway, which shares steps with both NHEJ and homologous recombination.

How does competition between HR and NHEJ occur?

Obviously, a competition between HR and NHEJ components may be one of the aspects that arises. In addition, systems in which multiple DSBs or SSBs are introduced trigger the activation of DDR, NHEJ, and HR pathways by altering the kinetics of the association with DNA damage, the chromatin, and nuclear scaffold, as well as with each other.

How many nucleotides do alt-NHEJ events use?

Many alt-NHEJ events use short patches of terminal microhomology (5–25 nucleotides) for ligation ( McVey & Lee, 2008 ).

How are error prone repair pathways compensate for loss of HR?

Error-prone repair pathways can compensate for the loss of HR. Polθ (an alt-EJ polymerase) is upregulated in HR-deficient cancers: loss of the HR and Polθ-mediated alt-EJ pathways is synthetic lethal. DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genomic integrity.