Genomic Instability and DNA Replication Mechanisms

Genomic instability arises when the faithful duplication and transmission of DNA is compromised, leading to mutations, chromosomal rearrangements and copy number variations with broad implications for human disease, ageing and evolutionary adaptation. Central to maintaining genome integrity is the orchestration of DNA replication, wherein the replication fork advances along the template strands to synthesise new DNA. Perturbations in this process—such as replication stress, encounter with DNA secondary structures and obstacles to fork progression—can trigger fork stalling, collapse and the activation of DNA damage response pathways. Multiple repair and tolerance mechanisms, including homologous recombination, mismatch repair and base excision repair, coordinate to resolve replication-associated lesions, restart stalled forks and prevent deleterious repeat expansions. Particular vulnerability is observed at repetitive and structure-forming sequences, such as trinucleotide repeats and GAA•TTC tracts, which can adopt non-B DNA conformations and impede polymerase movement. The interplay between replication dynamics and repair activities underpins cellular capacity to safeguard genetic information and informs our understanding of tumourigenesis, neurodegeneration and potential therapeutic interventions.

Research from Nature Portfolio

Recent studies have demonstrated that structure-forming CAG/CTG repeats generate potent barriers to DNA gap repair, resulting in both repeat length instability and chromosome breakage. Employing a novel assay that monitors single-strand resection and gap fill-in across expanded repeats, it was shown that repeats on the template strand inhibit resection and provoke expansions, whereas repeats on the resected strand increase contractions and large-scale deletions. Modulation of nucleolytic processing factors rescued instability, while homologous recombination proteins exhibited protective roles on single-stranded DNA. These findings illuminate the mechanistic basis by which repetitive sequences impede replication and repair, contributing to genomic fragility and mutation accumulation.

Genomic Instability and DNA Replication Mechanisms publication trend

The graph below shows the total number of articles in genomic instability and dna replication mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Genomic instability: Propensity of the genome to acquire mutations and structural alterations during DNA replication and repair.

Replication fork: The junction at which parental DNA strands are unwound and copied by polymerases during DNA replication.

Non-B DNA structures: Alternative DNA conformations, such as hairpins and triplexes, that deviate from the canonical B-form helix and impede replication.

Homologous recombination: A high-fidelity repair pathway that uses a homologous DNA sequence as a template to repair breaks and restart stalled replication forks.

Base excision repair: A mechanism that removes damaged bases via specialised enzymes and restores integrity through subsequent gap filling and ligation.

Replication stress: Conditions that challenge normal fork progression, including DNA lesions, secondary structures and shortage of replication factors.

References

1. Structure-forming CAG/CTG repeats interfere with gap repair to cause repeat expansions and chromosome breaks. Nature Communications (2023).
2. Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers. Nucleic Acids Research (2023).
3. Replication stress at microsatellites causes DNA double-strand breaks and break-induced replication. Journal of Biological Chemistry (2020).