DNA damage identification and its repair are decisive for maintaining normal cell function and activity. The DNA in the cell is constantly suffering from various hazards inside and outside the cell, and various damages often occur in the DNA. DNA damage is recognized as a key factor leading to cellular aging and its functional disorders. Intracellular DNA damage is not repaired in time, and DNA damage is accumulated in the cells, which leads to genetic instability in the cells and even increases the risk of cancer. DNA damage recognition is the only way cells can recognize their own DNA damage. The identification of intracellular DNA damage is accomplished by polyadenylation diphosphate ribosyltransferase (PARPs) family enzymes. They bind to the damaged DNA and modify the negatively charged poly(ADP-ribose) ribose polymer on the receptor protein to activate a series of subsequent cellular processes to complete the DNA damage signal recognition and delivery process. After the cells have recognized damage to the internal DNA, they will initiate a repair mechanism for the damaged DNA. DNA repair is a decisive factor in maintaining gene continuity and normal cell function. There are four major DNA repair pathways known, and the most important one is base excision repair (BER), which is the mechanism by which cells respond to most DNA damage. Uracil DNA glycosylase (UDG) is a class of important BER enzymes responsible for repairing uracil in DNA due to base damage.
DNA damage recognition process
After DNA damage occurs in cells, in order to prevent damage to DNA from entering the transcriptional translation process, cells must first recognize changes in the DNA chain. Only after the cells sense their DNA damage, after a series of intracellular signaling, the cells can initiate downstream DNA repair mechanisms. The identification of intracellular DNA damage is accomplished by polyadenylate diphosphate ribosyltransferase (PARPs) family enzymes, which bind to damaged DNA and activate a series of subsequent cellular processes to complete DNA damage signal recognition and Pass the process. As a key ribozyme that recognizes intracellular DNA damage and maintains gene integrity, PARPs are involved in a variety of cellular activities, including DNA repair, transcription, chromosomal structural regulation, energy metabolism, and intracellular signaling. In most cases, PARPs remain silent. They are activated when chromosomal DNA is damaged, specifically recognize and bind to the damaged chromosomal DNA strand, and use NAD+ as a raw material to catalyze a series of reactions of the receptor protein or itself. The long-chain negatively charged biopolymer polyadenosine diphosphate ribose chain (PAR) is formed on the relevant nuclear protein, which regulates the chromosome structure, makes it loose, exposes the internal damaged DNA, and completes the function recognition and signal transmission.
Figure 1. The PAR of chromosomal proteins makes the chromosome structure loose.
Repair of DNA damage
DNA damage repair is a phenomenon in which DNA molecules in biological cells are damaged after being damaged by various enzymes. DNA damage repair studies can help to understand the mechanism of gene mutation, the cause of aging and cancer, and can also be applied to the detection of environmental carcinogens.
Figure 2. DNA damage can be caused by ultraviolet light.
After the cells have been identified by PARP recognition, the signal is passed to downstream DNA repair-related enzymes, and a series of DNA repair mechanisms are activated. Repair of DNA damage is critical to maintaining genomic integrity, while different types of DNA damage are repaired by different DNA repair mechanisms. There are four major DNA repair pathways known, (1) base excision repair (BER); (2) nucleotide excision repair (NER); (3) double bond break repair (Double strand break repair, DSBR); (4) mismatch repair (MMR). Different repair pathways are achieved by different repair enzymes, and the mechanisms are quite different.
Base excision repair
One of the most important DNA repair pathways is base excision repair, which is the mechanism by which cells respond to most DNA damage. DNA damage caused by external factors (such as alkylation and oxidation) in eukaryotic cells is repaired by base excision. Base excision repair is not only an important repair method for maintaining nuclear DNA stability, but also the most representative repair mode in mitochondria. Studies have shown that an average of 10,000 base damage per cell per day is repaired by the base excision process. The BER process is coordinated by a series of enzymes such as DNA glycosidase, AP site resection enzyme, DNA polymerase and DNA ligase. The base excision repair process is initiated by the base glycosidase and is coordinated by a synergistic catalysis of enzymes such as DNA polymerase, AP site resection enzyme, and DNA linkase. The process can be divided into 4 steps: (1) Identification and removal of the wrong base: recognition of the corresponding incorrect base by the DNA glycosylation enzyme with specific recognition function, catalyzing the N-glycosidic bond between the base and the DNA backbone Hydrolysis breaks, releasing the wrong base. (2) Depyrimidine/purine base site formation (AP site): catalyzed by AP endonuclease, the glycosidic-phosphate bond of the wrong nucleotide is cleaved, and then catalyzed by deoxyribose phosphodiesterase Five carbon sugar. (3) Implantation of correct nucleotides: Under the catalysis of DNA polymerase, the correct nucleotides are implanted into the DNA strand breaks to synthesize new fragments. (4) Re-linking of DNA strands: Under the catalysis of DNA linkase, the two complementary strands that are broken are re-linked to complete the entire base excision repair.
Figure 3. Schematic diagram of the base excision repair (BER) process.
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