DNA replication stress

DNA Replication Stress

Replication stress and its consequences in mitosis

DNA replication stress refers to the slowing or stalling of the DNA replication process, which can lead to genomic instability. This phenomenon is a significant concern in both normal cellular processes and in the context of cancer development. Replication stress can arise from various sources, including DNA damage, difficult-to-replicate sequences, and insufficient supply of deoxyribonucleotide triphosphates (dNTPs).

Causes of DNA Replication Stress

Replication stress can be induced by several factors:

• DNA Damage: Lesions such as thymine dimers or double-strand breaks can impede the progression of the replication fork.
• Replication Fork Barriers: Natural barriers such as telomeres, centromeres, and highly transcribed regions can cause stalling.
• Oncogene Activation: Overexpression of oncogenes can lead to increased replication origin firing, depleting dNTP pools and causing stress.
• Chromatin Structure: Tight chromatin can hinder the progression of replication machinery.

Consequences of Replication Stress

INO80 stabilizes replication forks and counteracts mislocalization of H2A.Z

When replication stress occurs, it can lead to several cellular consequences:

• Fork Collapse: Prolonged stalling can result in the collapse of replication forks, leading to double-strand breaks.
• Genomic Instability: Accumulation of DNA damage and improper repair can cause mutations and chromosomal rearrangements.
• Cell Cycle Arrest: Activation of the DNA damage response can halt the cell cycle to allow for repair.
• Apoptosis: If damage is irreparable, cells may undergo programmed cell death.

Cellular Responses to Replication Stress

Cells have evolved mechanisms to cope with replication stress:

• Checkpoint Activation: The ATR and CHK1 pathways are crucial for detecting and responding to replication stress.
• Fork Stabilization: Proteins such as BRCA1 and BRCA2 help stabilize stalled forks and facilitate repair.
• Translesion Synthesis: Specialized DNA polymerases can bypass lesions to allow replication to continue.

Replication Stress in Cancer

Rationale for enhancing replication stress to kill cancer cells

Replication stress is a hallmark of cancer cells, which often exhibit high levels of genomic instability. Cancer cells frequently experience replication stress due to:

• Oncogene-Induced Replication Stress: Oncogenes can drive excessive replication, leading to stress.
• Defective DNA Repair: Many cancer cells have mutations in DNA repair pathways, exacerbating stress.

Therapeutic Targeting of Replication Stress

Illustration of various approaches to target replication stress for cancer treatment

Exploiting replication stress is a promising strategy in cancer therapy:

• PARP Inhibitors: These drugs target cancer cells with defective homologous recombination repair.
• ATR/CHK1 Inhibitors: Inhibiting these pathways can enhance replication stress, selectively killing cancer cells.
• dNTP Pool Modulation: Altering nucleotide availability can increase stress in cancer cells.

Related Pages

• DNA replication
• Genomic instability
• DNA damage response
• Cancer