DNA is the most important genetic material of biology, and its integrity is related to the accuracy of genetic information. However, DNA damage is often accompanied in the body. It is mainly caused by endogenous factors (replication errors, oxidative deamination and active oxygen substances) and exogenous factors (UV and radiation) that cause abnormalities in the chemical structure or coding characteristics of DNA, thus forming DNA damage. If it is not repaired in time, cells will have physiological abnormalities due to genetic information errors. There are many types of DNA damage, including single-strand breaks (SSBs), double-strand breaks (DSBs), phosphate diester bond breaks, and base damage (pyrimidine dimers, mismatches, and crosslinks).
In order to deal with the threat caused by DNA damage, cells have evolved a variety of mechanisms, collectively called DNA Damage Response (or DNA damage repair，DDR), to detect DNA damage, indicate the existence of damage and promote damage repair.
DDR has seven main repair forms：
1. Non-homologous End-joining，NHEJ；
2. Homologous Recombination Repair，HRR；
3. Nucleotide Excision Repair，NER；
4. Fanconi Anemia，FA；
5. Translesion Synthesis，TLS；
6. Base Excision Repair，BER；
7. Mismatch Repair，MMR.
For DSB, DNA is mainly repaired through NHEJ and HRR. NHEJ is simpler than HRR, which can directly connect the two ends of the broken DNA. So, it is easy to have inaccurate repair, while HRR is much more complex, which can repair serious DNA damage. Which pathway is activated depends on many factors, such as the structure of damaged DNA, repair difficulty and cell cycle.In the NHEJ pathway, Ku70 and Ku80 form a heterodimer, which attracts the recombinant enzyme Artemis, and then gathers DNA PKcs, XRCC4, LIG4 and XLF to form a complex (Fig. 1), finally completing the repair process.
In HRR , DSB is first identified by ATM or ATR, and Mre11, Rad50, and Nbs1 are recruited to form the MRN complex. MRN cleaves the ends of DNA to form single-strand DNA(ssDNA). Subsequently, RP-A coated ssDNA to avoid its degradation by nuclease. Through a series of complex regulation, RP-A is covered and replaced by RAD 51. RAD51 enters the DNA double stranded template, pairs with homologous DNA sequences to form a D-Loop structure, and the D-Loop extends or connects with another end to complete the repair process（Fig. 2）. Many tumor suppressor genes, such as BRCA1, BRCA2, and Histone H2A. X, are involved in this pathway.
In addition to NHEJ and HRR, there is also a selective non-homologous end joining，which called ‘microhomology-mediated end joining’ (MMEJ), also known as ‘Alternative NHEJ’ (Alt NHEJ). At the DNA break, PARP1 is recruited by the MRN complex, and then repaired by POLQ. XRCC1 and LIG1/3 complete the connection (Fig. 3).
NER is mainly used to repair SSB, mainly including the massive damage of spiral twist. DNA replication and transcription can also be repaired through NER when blocked. The most common repair process is to cut the damaged chain first by endonucleases XPF-ERCC1 and XPG, POL δ/ε Repair the damage, and then connect it through LIG1.The FA and TLS pathways are mainly aimed at DNA strand crosslinks (Interstand Cross-links, ICL). They create a double break gap by cutting the main chain of phosphodiester surrounding the strand crosslinks, and then repair the damage through homologous recombination. CMG helicase complex (CDC45+MCM2~7+GINS) is involved in this process. At present, 22 FANC related proteins have been identified to participate in the regulation of this pathway.
BER mainly aims at the oxidative damage of base and repairs it by chromatin remodeling. During the removal of damaged base, 11 different DNA glycosylases are involved. After the removal, a base free site is generated. POLβ will bind to this site and complete the repair by combining LIG1 or LIG3 with XRCC1 to form a complex.The DNA damage caused by nucleotide mismatch is mainly repaired by the MMR pathway, and the damage is recognized by MSH2/MSH6 or MSH2/MSH3 complex. The mismatch part of the daughter chain is recognized and removed by exonuclease EXO1 according to the difference between the degree of methylation of the mother chain and the daughter chain.
DDR has multiple pathways, involving hundreds of proteins to perform corresponding functions in each link, among which ATM, ATR and DNA PKcs are key proteins to detect DNA damage. These kinases and checkpoint kinases reduce the activity of cyclin dependent protein kinase (CDK) through a variety of mechanisms. At the same time, activating p53 can also regulate the activity of CDK, thereby inhibiting the cell cycle process. For tumor patients lacking specific DDR function, targeted therapy based on inhibition of DDR response is becoming more and more popular, such as targeting tumor cells that kill BRCA1 or BRCA2 mutations with poly ADP ribose polymerase (PARP) inhibitors.