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hat is "DNA protein cross-linking" and why is it so critical to cancer research
In genetics, "DNA protein cross-linking" refers to the process when a variety of exogenous or endogenous agents react with two nucleotides in DNA to form covalent links. This cross-linking can occur within the same DNA strand (internal strand) or between opposite strands of double-stranded DNA (external strand). These attachments can hinder the cell's metabolic processes, such as DNA replication and transcription, and even trigger cell death. However, these cross-links can also be repaired through excision or recombination pathways. DNA cross-linking has important applications in chemotherapy and treatments that target cancer cells to trigger apoptosis, and is also valuable in understanding how proteins interact with DNA.
Types of cross-linking agents
Many of the cross-linkers that have been characterized have two independently reactive groups within the same molecule, each of which is capable of binding to a nucleotide residue of DNA. These agents are divided into exogenous and endogenous cross-linking agents based on their origin.
Exogenous cross-linkers refer to chemicals and compounds derived from environmental exposure, whether natural or synthetic.
Endogenous cross-linkers are compounds and metabolites derived from cells or biochemical pathways.
Exogenous cross-linking agent
Nitrogen essentials are exogenous alkyl agents that react with the N7 position of guanine in the base. They have a bis(2-ethyl chloride)amine core structure and varying R groups. These two reactive functional groups can alkylate nucleotides and form cross-linked lesions. These agents are often introduced as drugs and used in cytotoxic chemotherapy.
Cisplatin (cisplatin) and its derivatives mainly act on adjacent guanine, and its N7 position is the main reaction site.
In addition to cisplatin, cross-linking agents such as chloroethyl nitrourea (CENU) are widely used in chemotherapy, especially for brain tumors. Psoralens are natural compounds found in plants that cross-link with DNA under the action of ultraviolet A (UV-A).
Endogenous cross-linking agent
Endogenous cross-linking agents such as nitrite are formed in the gastrointestinal tract as by-products of dietary nitrite. These cross-linkers form cross-linked lesions by converting amino groups in DNA to carbon groups.
During cellular biochemistry, lipid peroxidation and prostaglandin biosynthesis trigger the production of reactive chemicals that further trigger DNA cross-linking.
A variety of clinical applications will follow, such as special methods of using DNA cross-linking agents to target cancer cells in chemotherapy.
Repair of DNA cross-links
Cross-linked DNA requires various enzymes and other factors in the cell to repair, including the nucleotide excision repair (NER) pathway and homologous recombination. The operation of these repair mechanisms is critical to maintaining cell health, as unrepaired cross-links can lead to severe genomic instability and the development of cancer.
Application of cross-linking
In clinical treatments, the formation of DNA cross-links offers a novel way to fight cancer. By blocking DNA replication in cancer cells by targeting specific nucleotides, this approach appears to reduce side effects.
Currently, these cross-linking agents have been gradually used in chemotherapy related to lung cancer. Especially in the treatment of non-small cell lung cancer (NSCLC), these cross-linking agents have shown unexpected effects.
As with the potential advantages shown by chemotherapy, lung cancer patients with low expression of the BRCA1 gene may have better survival rates after receiving titanium and rhenium therapy. In this way, the level of BRCA1 expression may be used as an important indicator for personalized chemotherapy.
It can be seen from the characteristics of various cross-linking agents that we have explored many possibilities in cancer research, and these possibilities have indicative significance for guiding future treatment. By studying how cross-linked cells repair damage and respond to treatment, can we find more effective cancer treatments?
