What is Replication Fork Stalling?
Replication fork stalling refers to the process where the progression of the replication fork is halted during DNA replication. This can occur due to various intrinsic and extrinsic factors such as DNA damage, tightly bound proteins, or secondary structures in the DNA. In the context of cancer, replication fork stalling is particularly significant as it can lead to genomic instability, a hallmark of cancer development.
DNA lesions such as thymine dimers or bulky adducts.
Replication stress, often induced by oncogene activation.
Inadequate supply of nucleotides or replication machinery components.
Endogenous factors like complex DNA secondary structures.
These factors impede the normal progression of the replication machinery, causing the fork to stall.
Why is Replication Fork Stalling Important in Cancer?
In cancer cells, replication fork stalling is particularly detrimental because it can result in
double-strand breaks (DSBs) and genomic instability. When replication forks stall, they can collapse if not properly resolved, leading to DSBs. Cancer cells often exhibit high levels of replication stress due to rapid proliferation and oncogene activation, making them more susceptible to fork stalling and subsequent genomic instability.
Fork stabilization: Proteins like BRCA1 and BRCA2 help stabilize the stalled fork, preventing collapse.
Fork restart: Pathways such as homologous recombination (HR) can facilitate the restart of stalled forks.
Translesion synthesis (TLS): Specialized DNA polymerases bypass lesions to allow replication to continue.
Activation of the
ATR/CHK1 pathway, which halts cell cycle progression to provide time for repair.
These adaptive responses are often hijacked in cancer cells to promote survival despite high levels of replication stress.
Formation of DSBs, which are highly deleterious and can lead to
chromosomal aberrations.
Genomic instability, contributing to cancer progression and resistance to therapy.
Cell death, particularly if the damage is irreparable and triggers apoptotic pathways.
Conclusion
Replication fork stalling is a critical event in the maintenance of genomic stability. In cancer, the high prevalence of replication stress exacerbates the potential for fork stalling, contributing to genomic instability and cancer progression. Understanding the mechanisms underlying replication fork stalling and resolution offers valuable insights into potential therapeutic targets, paving the way for more effective cancer treatments.
