DNA Damage Repair

DNA is the carrier of the genetic information that defines any living being. The genetic code fixed in DNA is crucial for processes on a subcellular scale up to the appearance and function of the organism as s whole. Nonetheless, DNA is constantly exposed to insults from endogenous sources such as hydrolysis, oxidation, alkylation, or replication errors. In addition, ionizing radiation, UV radiation, and a plethora of chemical reagents are external factors that threaten the integrity of DNA.

Unlike RNA and proteins, DNA is not being degraded and re-synthesized upon damage. Instead, various repair pathways are in existence to assure that the DNA remains intact. Francis Crick noted in 1974 that “we totally missed the possible role of enzymes in [DNA] repair. I later came to realize that DNA is so precious that probably many distinct mechanisms could exist.”

This presage holds true today: over a hundred genes have been characterized since that are involved in an intricate network of DNA repair pathways. DNA damage can be repaired via six different pathways depending on the nature of the lesion: chemical modifications, misincorporated nucleotides, and cross-links are reverted through direct reversal (DR), mismatch repair (MMR), and nucleotide excision repair mechanisms. DNA single strand breaks are being mended via base excision repair. Highly mutagenic DNA double strand breaks finally are repaired through a number of complex pathways that rely on homologous recombination (HR) with the sister chromatid (in the S or G2 phase of the cell cycle) or non-homologous end-joining (NHEJ) of both ends of the double strand break. In case a DNA lesion cannot be repaired in time, specialized DNA polymerases enable trans-lesion synthesis (TLS) in order to prevent the DNA replication fork from stalling. Mutations that render components of these repair pathways non-functional lead to diseases such as xeroderma pigmentosum, ataxia telangiectasia, Fanconi anemia, and a predisposition for cancer.

Besides, these repair mechanisms are of high interest for current targeted genome editing approaches that typically take advantage of the cellular DNA repair machinery.