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When DNA is in crisis: Why do wrong nucleotides cause replication blockage?
In the life course of a cell, DNA replication is an important process to maintain genetic integrity. However, this process can be hindered when DNA encounters various stresses, leading to what is known as replication stress. This stress is caused by a variety of factors and can cause a series of problems during DNA replication, which may ultimately lead to genome instability and the risk of cancer and aging.
DNA replication stress refers to the exposure of a cell's genome to various stress states. These events occur during DNA replication and may lead to replication fork stalling.
During normal DNA replication, the activities of DNA polymerase and helicase are crucial. However, this process can be disrupted when nucleotides are mistakenly incorporated into the DNA strand. This incorrect nucleotide causes structural abnormalities in the DNA, causing the replication fork to stall and fail to proceed successfully.
In addition, the occurrence of DNA cross-links is also an important factor in triggering replication stress. DNA cross-linking refers to the covalent connection between two DNA strands, which prevents the DNA strands from separating properly, leading to the stalling of replication forks. Repair of this phenomenon usually requires complex biochemical processes such as sequence cleavage and homologous recombination, in which proteins such as ATM and ATR that coordinate these processes play a crucial role.
ATM and ATR are proteins that help relieve replication stress, specifically as kinases that are recruited and activated after DNA damage.
The stability of replication forks is critical for efficient DNA replication. If regulatory proteins such as ATM and ATR cannot stabilize this fork, the replication fork will collapse, which will affect subsequent DNA repair and synthesis processes. In this case, cells may initiate reverse recombination to repair damaged DNA ends, which can have a significant impact on the cell's survival and reproduction.
Maintenance and repair of replication forks
In maintaining replication fork structure, the fork protection complex (FPC) is recruited to help stabilize and link. This complex functions to prevent further DNA damage when polymerase or helicase activity in cells is stalled.
When a replication fork is stalled by an interaction, phosphorylation of the protein can initiate a cascade of signals to prompt the restart of replication.
If cells face single-stranded DNA or DNA double-strand breaks, the function of these signaling pathways will be affected, possibly causing greater replication stress. When a link fails, it results in the production of more single-stranded DNA, which is the key needed to restart replication.
Challenges in restarting the replication process
Repair at DNA cross-links obviously requires the introduction of various DNA repair factors. These factors coordinate efforts to deal with problems during replication, such as repairing erroneous nucleotides or removing damaged bases.
Multiple DNA repair mechanisms operate along overlapping layers and can be recruited to the point of failure depending on the nature and location of the damage.
These repair pathways function not only to protect stalled replication forks but also to help restart damaged forks. However, when these repair mechanisms are imperfect, more severe replication stress and genetic instability may occur, which is a precursor to cancer.
Application and impact in cancer
Normal levels of replication stress can promote genetic instability, ultimately leading to tumor progression. However, higher levels of replicative stress may kill cancer cells. Some studies have shown that when checkpoints are inactivated, this increased stress can cause DNA replication in cancer cells to enter mitosis with defects, ultimately leading to cell death.
Reducing the intensity of oncogenic signals or enhancing DNA replication pressure may change the carcinogenesis potential and serve as a therapeutic approach.
This discovery has far-reaching significance for the treatment of cancer and provides inspiration for us to explore new treatment strategies. As we gain a better understanding of these biological processes, the way we diagnose and treat cancer may fundamentally change.
Faced with these challenges in the DNA replication process, can we find more effective ways to repair damage to the cell genome to prevent the occurrence of cancer?
