Helicase Functions in Genomic Stability and Aging

DNA helicases are specialised motor proteins that unwind duplex nucleic acids, enabling replication, repair and recombination. Central to genomic stability, helicases such as the RecQ family member WRN resolve complex DNA structures at stalled forks, facilitate choice between repair pathways and protect nascent strands from aberrant nucleolytic degradation. Dysfunction of these enzymes underlies progeroid syndromes, including Werner syndrome, characterised by premature senescence, telomere attrition and cancer predisposition. In ageing cells, helicase insufficiency leads to accumulation of DNA lesions, aberrant double-strand break repair and compromised stem cell function. Conversely, controlled modulation of helicase activity offers routes to precision medicine: synthetic lethality in mismatch-repair-deficient tumours and potential restoration of genome maintenance in ageing tissues. The interplay between helicase-driven fork recovery, pathway switching in end-processing and telomere maintenance illustrates a nexus linking genome integrity to organismal lifespan.

Research from Nature Portfolio

Recent studies have validated WRN helicase as a therapeutic target in cancers with microsatellite instability. A novel allosteric inhibitor locks WRN in an inactive conformation, selectively inducing DNA damage and tumour regression in preclinical models without affecting microsatellite-stable cells. Foundational work has elucidated how WRN steers repair at double-strand breaks: its helicase and exonuclease activities promote classical non-homologous end joining while suppressing alternative end joining, thereby preventing large deletions and telomere fusions. Further mechanistic insight reveals that CDK1-dependent phosphorylation of WRN is essential for long-range resection at collapsed replication forks, favouring homology-directed repair over end-joining and ensuring efficient replication recovery and chromosomal stability.

Helicase Functions in Genomic Stability and Aging publication trend

The graph below shows the total number of articles in helicase functions in genomic stability and aging across all publications each year (not limited to Nature Index journals).

Technical terms

Helicase: An enzyme that translocates along nucleic acid strands, unwinding duplex DNA or RNA using energy from nucleotide hydrolysis.

Replication fork: The Y-shaped structure formed during DNA replication where parental strands are separated to serve as templates.

Double-strand break (DSB): A severe form of DNA damage where both strands of the helix are severed, requiring precise repair to maintain genome integrity.

Non-homologous end joining (NHEJ): A repair pathway that rejoins broken DNA ends directly, subdivided into classical and alternative mechanisms with distinct genetic requirements.

Synthetic lethality: A cellular vulnerability exploited when simultaneous impairment of two genes or pathways leads to cell death, whereas disruption of either alone is tolerated.

Telomere: Repetitive DNA sequences at chromosome ends that protect genomic termini from degradation and inappropriate repair.

Senescence: A stable state of cell cycle arrest accompanied by characteristic changes in gene expression, morphology and secretory profile.

References

1. Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers. Nature (2024).
2. WRN regulates pathway choice between classical and alternative non-homologous end joining. Nature Communications (2016).
3. The WRN exonuclease domain protects nascent strands from pathological MRE11/EXO1-dependent degradation. Nucleic Acids Research (2015).
4. CDK1 phosphorylates WRN at collapsed replication forks. Nature Communications (2016).
5. Specific Monitoring the DNA Helicase Function via Anchor‐Embedded DNA Probe. Advanced Science (2024).
6. Amelioration of premature aging in Werner syndrome stem cells by targeting SHIP/AKT pathway. Cell & Bioscience (2025).