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Facing genetic damage: How does DNA repair crosslinks using homologous recombination?
In the world of biology, the state of DNA is closely related to health. DNA replication stress refers to a state in which the cellular genome is exposed to various stresses, which usually occur during DNA replication and may lead to the stalling of replication forks. There are many causes of replication stress, including incorrectly inserted ribonucleotides, abnormal DNA structure, or even conflicts between replication and transcription.
Common triggers include deficiencies in key replication factors, and overexpression or persistent activation of oncogenes may also lead to genomic instability.
ATM (auto-repair gene) and ATR (adenylate acylase) are two proteins that can help relieve replication stress. These proteins are recruited and activated upon DNA damage. When these regulatory proteins fail to stabilize the replication fork, it collapses and then initiates the repair process of the damaged DNA ends.
The structure and function of the replication fork
The replication fork is composed of a group of proteins that influence the activity of DNA replication. For replication fork stalling, the cell must have a certain number of stalled forks and the length of the stall. The replication fork specifically pauses when the helicase and polymerase activities cease. In this case, the fork protection complex (FPC) is recruited to help maintain the junction.
In addition to pausing and maintaining fork structure, protein phosphorylation can also generate signaling cascades to restart replication. Mrc1, a protein in FPC, transmits checkpoint signals by interacting with kinases in the signaling pathway. When the function of these kinases is impaired, excess single-stranded DNA is produced, which is necessary to restart replication.
Remove replication barriers
DNA interstrand crosslinks (ICLs) induce replication stress by impeding the progression of replication forks, leading to failure of DNA strand separation and stalling of replication forks. Repair of ICLs can be performed by sequential cleavage and homologous recombination. In vertebrate cells, replication of chromatin templates containing ICLs triggers the recruitment of more than 90 DNA repair and genome maintenance factors.
Analysis of proteins recruited to stalled replication forks revealed a specific set of DNA repair factors involved in the replication stress response. Among them, SLF1 and SLF2 were found to physically link the SMC5/6 DNA repair complex to RAD18.
Replicate-related repair mechanisms
Mechanisms that process damaged DNA in a coordinated manner with the replication fiber machinery are considered an example of replication-associated repair. While repairing DNA interstrand crosslinks, multiple DNA repair processes may be recruited, depending on the nature and location of the damage. These repair processes include: removing incorrectly inserted stacks, removing incorrectly inserted ribonucleotides, removing damaged stacks that hinder the replicative polymerase, etc.
Importance of single-strand break repairSingle-strand breaks are one of the most common forms of endogenous DNA damage. When a nick in the guide strand causes replication fork collapse, a debonded single-ended double-strand break is generated, which can be repaired by homologous recombination.
Factors that cause replication stress
Replication stress arises from a variety of endogenous and exogenous stresses that frequently affect the genome. These stresses include not only DNA damage but also overly compacted chromosome structure (which renders the replication machinery inaccessible) and overexpression of oncogenes. These conditions increase genomic instability and are associated with cancer and aging.
Application in cancer
Normal replication stress at low to moderate levels promotes genomic instability, which may lead to tumor formation. But high levels of replication stress can kill cancer cells. Studies have shown that when checkpoints become dysfunctional, replication stress increases, which may cause incomplete or incorrect DNA replication when cancer cells enter the mitosis phase, ultimately leading to cell death.
In addition, the study examined the effect of replication stress on the activity of APOBEC3B, an enzyme that can mutate the oncogenome in various types of cancer. The results show that weakening oncogene signaling or enhancing DNA replication pressure can change the carcinogenic potential and has potential therapeutic applications.
These findings highlight the importance of DNA repair processes. Could these repair mechanisms provide a solution to the constant threats to our genome?
