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The guardian of DNA repair: What is the importance of NEDD8 in damage repair?
DNA damage is a common phenomenon in the course of life. DNA may be damaged during cell division, environmental stimulation or daily metabolism. At this point, cells must repair themselves quickly and efficiently to ensure genetic stability. In recent years, scientists have discovered a protein called NEDD8 that plays a key role in DNA damage repair. As a ubiquitin-like protein, NEDD8 modifies specific proteins through a process called NEDDylation, thereby affecting various physiological processes of the cell.
"NEDD8 modification is closely related to a variety of biological processes, not only limited to DNA repair, but also involved in the progression of the cell cycle and the regulation of the cytoskeleton."
The main function of NEDD8 is to bind to Cullins (Cullin family proteins), which are the main components of ubiquitin E3 ligases. These cullins must undergo NEDDylation to function properly and regulate the ubiquitination process, so the activation of NEDD8 is essential for DNA damage repair.
Activation and binding process of NEDD8
Like ubiquitin and SUMO proteins, the activation and conjugation of NEDD8 require processing at its C-terminus. The activation E1 enzyme of NEDD8 is composed of two subunits, APPBP1 and UBA3. The heterodimer formed by the combination of the two can form a high-energy thioester intermediate in an ATP-dependent reaction, and then transfer the activated NEDD8 to UbcH12 E2 enzymes, which eventually bind to different substrates. The key lies in the presence of E3 ligase, which is also a necessary condition for NEDD8 modification.
The role of NEDD8 in DNA repair
The latest research shows that the accumulation of NEDD8 at sites of DNA damage is a very dynamic process. In particular, modification of NEDD8 plays a key role in the processes of global genome repair (GGR) and nucleotide excision repair (NER). When cells are damaged by UV radiation, the CUL4A protein is activated by NEDD8, which then performs DNA repair to remove the damaged parts.
In addition, NEDD8 also plays a role in the repair of double-strand breaks. Non-homologous end joining (NHEJ) is the main pathway for repairing double-strand breaks. In this process, Ku70/Ku80 heterodimers form a stable ring structure around the DNA ends. However, after the repair process is completed, the ring must be removed. This heterodimer would otherwise block transcription or replication. At this time, Ku heterodimers are ubiquitinated in a DNA-damage and NEDDylation-dependent manner, promoting the release of Ku and other NHEJ components.
"NEDD8 modification during DNA repair is not only the beginning of repair, but also an important indicator for ensuring cell health."
NEDD8 and cancer treatment
As the research deepened, scientists found that during the progression of cancer, the silencing of DNA repair genes may be caused by hypermethylation of their promoter regions, which further exacerbates genetic instability and increases the risk of cancer cells. A substantial increase. Among various cancers, 17 common cancers showed low expression of DNA repair genes, such as chronic myeloid leukemia.
Activation of NEDD8 is critical for DNA repair pathways. If NEDD8 activation is inhibited, cells may die due to decreased repair capacity, leading to the accumulation of genetic damage. This may be more pronounced in cancer cells than in normal cells, particularly if the cancer cells already have DNA repair defects due to prior epigenetic modifications. Studies have shown that Pevonedistat (MLN4924), a drug that inhibits NEDD8 activation, has shown good efficacy in clinical trials.
NEDD8 in preclinical studies
In experiments in mice, the study showed that Pevonedistat was able to inhibit the activation of NEDD8, thereby preventing obesity and related glucose intolerance caused by a high-fat diet. Similarly, NEDD8 also regulates NF-κB, and its activation process depends on the degradation of IκB protein, which also requires the participation of NEDD8. By inhibiting NEDD8, not only was the nuclear translocation of NF-κB affected, but the survival of mice was also prolonged.
Throughout the research on NEDD8, this protein has shown its importance at all levels of life, especially in maintaining the integrity of DNA and the stability of cells. How will NEDD8 affect future cancer treatments? Will it be the key to new anti-cancer strategies?
