DNA damage repair mechanism

DNA is the main carrier of biological genetic information, and its stability is of vital importance for maintaining the health of living organisms. During the life of a cell, many endogenous factors such as base oxidation, deamination, and exogenous factors such as ultraviolet light, ionizing radiation, and carcinogenic compounds can cause DNA damage. According to the repair pathway, DNA damage can be divided into DNA double-strand damage (including NHEJ and HR repair pathways), base excision repair, nucleotide excision repair, mismatch repair, and other ways. Interestingly, cells do not mobilize an isolated DNA repair pathway when repairing the damage. These pathways regulate and assist each other to maintain the stability of genetic information.

DNA is subjected to various factors such as DSB (DNA double-strand damage), SSB (DNA single-strand damage), and oxidation, methylation, mismatch, interchain or intrachain crosslinking of bases, and The repair pathways that cells call for different types of damage, such as NHEJ (non-homologous recombination end joining), HR (homologous recombination), BER (base excision repair), NER (nucleotide excision repair).

DNA Double-Strand Break is the most harmful type of DNA damage. Events that cause DNA double-strand damage, such as ionizing radiation (IR) and topoisomerase inhibitors, are also widely used in cancer treatment. Other types of DNA damage can directly or indirectly cause DNA double-strand damage. For example, during cell replication, the replication fork proceeds to DNA single-strand damage or interstrand cross-linking, which further produces DNA double-strand damage. This effect plays an important role in the treatment of cancer because the killing mechanism of many chemotherapeutic drugs is to kill cells after the DNA original damage caused by DNA double-strand damage. The primary repair pathway for DNA double-strand breaks is non-homologous recombination end joining (NHEJ) and homologous recombination (HR). The NHEJ repair pathway is activated by DNA-PKcs and can be performed at any cell cycle, but it does not guarantee the accuracy of the repair results; HR is regulated by ATM, only in the S phase with sister chromatid decondensation and The exact repair method that can be performed in G2. HR is the primary pathway for lower eukaryotic repair of double-stranded damage, and NHEJ is the primary means of mammalian cell repair. However, HR plays an extremely important role in repairing double-strand damage caused by replication fork collapse and interchain cross-linking in the S phase of the Cell cycle.

Base Excision Repair is a type of pathway that removes damaged bases such as N-alkylated hydrazine and 8-OxoG. The specific glycosidase recognizes and clears the damaged base, and a site of depurination or a pyrimidine is exposed, followed by APE1 or other glycosidase excision of the nearby region to cause DNA single-strand damage, and then, depending on the length of the deleted DNA, Repair by XRCC1, PARP1 or PCNA.

Nucleotide Excision Repair is responsible for scavenging the large groups attached to DNA, such as damage caused by UV irradiation and cross-linking between chains. At the same time, NER is the first step in cross-link cross-linking repair to help homologous recombination pathways. Going on. Nucleotide excision repair is divided into transcription-dependent removal of damage-inhibiting RNA polymerase extension and genome-wide resection repair independent of transcription. The pathway molecule includes a family of XP proteins that recognize DNA damage sites, XPG and ERCC1-XPF proteins that cleave damaged regions, and DNA ligase I at the splicing break.

Mismatch Repair is responsible for eliminating mismatches caused by replication and base modifications such as methylation or oxidative bases caused by spontaneous or drug induction. Mismatch repair recognizes the injury site by the MutS? complex composed of MSH2 and MSH6 proteins, binds to the MutL? complex composed of MLH1 and PMS2, and then excises the DNA containing the mismatched region by Exo1, and finally fills the deletion by DNA polymerase Pol?. The place.

All of the above DNA damages trigger a variety of DNA damage responses and maintain DNA stability. In the early stage of the injury, the DNA damage reaction can cause the cells to detect adverse factors in the environment and block the cell cycle, thereby avoiding further damage to the genetic material. Second, the DNA damage response mediates the repair of damaged DNA and maximizes the genetic information of the organism through various repair pathways. Finally, when DNA damage is too severe or impossible to repair, DNA damage triggers apoptosis, ensuring that cells with damaged DNA cannot survive and proliferate. Because of the importance of these pathways, the dysfunction of DNA damage responses can lead to a variety of human diseases. For example, mutations in the DNA repair pathway can be extremely sensitive to ultraviolet light, ionizing radiation, or DNA cross-linkers, while abnormalities in the apoptotic pathway can cause cells with severely damaged DNA to survive and increase the likelihood of cancer. On the other hand, since many anticancer drugs exert their killing effects by damaging the DNA of cancer cells, one can specifically improve the therapeutic effect of cancer by precisely regulating the DNA damage response.

Rosie Liu is working as an editor in Cusabio, a manufacture of antibodies, proteins, Elisa kits and related reagents for research use.