DNA repair processes are indispensable for maintaining the integrity of genetic information in all organisms. Environmental agents such as chemicals, UV light, and ionizing radiation, as well as endogenous metabolic processes involving DNA constantly challenge the chemical structure and stability of the genome. DNA lesions can interfere with processes such as DNA replication or transcription and may lead to mutations and cancer [1
]. To prevent the erosion of the chemical structure of DNA, living systems have evolved various different biochemical systems for DNA repair [3
DNA damage from endogenous sources gives rise to 20,000 lesions per mammalian cell per day. Amongst these lesions, the most common are base deamination, spontaneous hydrolysis of the N
-glycosidic bond, alkylation, and damage by reactive oxygen or nitrogen species and lipid peroxidation products [8
]. Other lesions such as the formation of single- and double-strand breaks, the collapse of replication forks, and the introduction of modified nucleic acid bases during DNA replication are caused by errors in DNA metabolic processes. In total, there are 1016
DNA repair events that occur daily in a healthy adult man (1012
]. Lesions that are not repaired often lead to mutations, aging and various diseases, including carcinogenesis and neurodegeneration [14
]. Some pathological disorders directly related to defects in the DNA repair machinery are Xeroderma pigmentosum, different types of cancer (breast cancer, colorectal cancer, endometrial cancer, gastric cancer, or prostate cancer), Fancomi anemia, Muir-Torre syndrome, Tay syndrome, and Werner syndrome. On the other hand, unrepaired lesions that occur in germline cells become the main source of genetic variability and therefore a driving force for the evolution. For this reason, the DNA repair system needs not only to be regulated to maintain an individual genome's integrity, but also to increase the genetic variability in the context of populations. Many mechanisms are known that regulate the amount of DNA repair as a response to environmental conditions [19
Given its many duties in different contexts, it is not surprising that DNA repair is a very complicated process, involving many factors. For instance to date, 168 genes encoding proteins involved in DNA repair have been identified in the human genome [17
] (20 January 2011, date last accessed). Over all organisms, there are many more; for base excision repair alone, KEGG [21
] lists 41 groups of orthologous genes encoding for hundreds of proteins in total. The key players in DNA repair are enzymes that catalyze reactions leading from the DNA with damage to a repaired molecule. They are assisted by proteins that detect damage and mediate signals that coordinate the repair process with other cellular processes. From the point of view of the DNA substrate, the biochemical pathways of DNA repair can be divided into eight categories:
- DNA damage signaling (DDS): also known as the DNA damage checkpoint; it is a group of responses to DNA damage caused by some endogenous and environmental agents; activation of these pathways may be triggered by the effect the DNA lesions have on replication, transcription, or chromatin topology;
- base-excision repair (BER): initiated by excision of a modified base from the DNA. Depending on the length of DNA resynthesis, the pathway is subdivided into two subpathways: short path (SP-BER) or long path (LP-BER);
- DNA damage response (DDR): directly restores the native nucleotide residue by removing the nonnative chemical modification;
- homologous recombination repair (HRR): repair of DNA double-strand breaks using the homologous DNA strand as a template for resynthesis;
- mismatch repair (MMR): postreplicational DNA repair that removes errors introduced during the replication (misinserted nucleotides, small loops, insertions, deletions);
- nonhomologous end-joining repair (NHEJ): ligation of ends resulting from DNA double-strand breaks (including the more error-prone microhomology-mediated end-joining (MMEJ) mechanism;
- nucleotide excision repair (NER): removes bulky damage from the DNA. The damage from the active strand of transcribed genes is removed by transcription coupled repair (TCR)-NER, while global genome repair (GGR)-NER removes damage present elsewhere in the genome;
- translesion synthesis (TLS): damage-tolerance pathway that employs specialized polymerases to replicate across lesions in order to finish replication despite DNA damage.
Each of these pathways can be represented as a series of enzymatic transformations between different DNA structures, catalyzed by a dedicated system of proteins. It must be emphasized that DNA repair pathways are connected to each other, that is, they can share some steps and/or proteins involved [13
]. As a consequence, DNA repair proteins rarely work in isolation in the cell, and their activity is dependent on other components of DNA repair systems.
DNA repair itself is not an isolated process, and it is strongly connected to other pathways of nucleic acid metabolism, including (but not limited to) DNA replication, DNA epigenetic modification, transcription, cell cycle regulation, and induced cell death as well as processes that are specific to different domains of life, such as telomere maintenance in eukaryotes and DNA restriction in prokaryotes.