DNA Damage & Repair

Cells are always under attack by potential mutagens, such as ionizing and UV radiation, genotoxic chemicals and by-products of cellular metabolism like reactive oxygen species and lipid peroxidation. Maintaining the integrity of its DNA is key to a species' ability to survive, so there are multiple signaling pathways and repair mechanisms to regulate genome quality control and repair. 

Upon the detection of DNA damage, several different responses can occur, including DNA damage repair, cell cycle arrest, checkpoint activation, transcription of effectors, autophagy, chromatin remodeling and apoptosis. (1) If the damaged DNA is not repaired, it could accumulate to lethal levels. This is why deficiencies in the DNA damage response system are often associated with different diseases and a predisposition to cancer.

The main methods of repairing DNA damage include mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER), non-homologous end joining (NHEJ) and homologous recombination (HR). (2)

DNA mismatch repair (MMR) finds and corrects base errors that occur during DNA replication and recombination and prevents them from becoming permanent in dividing cells. With mismatch repair, the mismatch creates a loop in the DNA that is recognized and repaired by nuclease-mediated single strand incision, followed by polymerase and ligase activity. (3)

Base excision repair corrects lesions in which the DNA helix is not significantly distorted, such as single damaged bases.  During G1 phase of the cell cycle after chromatin remodeling, the damaged base is recognized and removed by DNA glycosylase, and then the lesion is repaired by nuclease, polymerase and ligase activity. (4)

In contrast, nucleotide excision repair corrects bulky lesions in which the DNA helical structure is distorted. There are two kinds of NER: global genome NER, which surveys the whole genome for helix distortion and transcription-coupled NER, which targets lesions that block transcript elongation. A key difference between NER and the other single-strand DNA (ssDNA) repair systems is the excision of a 22–30 base oligo, rather than removal of a single base. The remaining ssDNA is then repaired by DNA replication machinery. (5)

Double stranded DNA breaks (DSBs) can result from exposure to ionizing radiation, free radicals, chemicals or from replication of a single-strand break. Double stranded breaks are repaired by homologous recombination or by non-homologous end joining. In homologous recombination, the sister chromatid serves as the template for repair, so this method can only occur during S phase or G2 of the cell cycle. (1)

Non-homologous end joining is a three-step process consisting of end binding and tethering, end processing and ligation. NHEJ can occur at any point in the cell cycle and because it does not require any sequence homology or short overhangs, the process is prone to errors and often results in small insertions or deletions. (6)

References

1. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009 Oct 22;461(7267):1071-8. doi: 10.1038/nature08467.
2. Chatterjee N, Walker GC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen. 2017 Jun;58(5):235-263. doi: 10.1002/em.22087.
3. Li GM. Mechanisms and functions of DNA mismatch repair. Cell Res. 2008 Jan;18(1):85-98. doi: 10.1038/cr.2007.115.
4. Dianov GL, Hübscher U. Mammalian base excision repair: the forgotten archangel. Nucleic Acids Res. 2013 Apr 1;41(6):3483-90. doi: 10.1093/nar/gkt076.
5. Schärer OD. Nucleotide excision repair in eukaryotes. Cold Spring Harb Perspect Biol. 2013 Oct 1;5(10):a012609. doi: 10.1101/cshperspect.a012609.
6. Lieber MR. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem. 2010;79:181-211. doi: 10.1146/annurev.biochem.052308.093131.