Helicase Function and Genomic Stability in DNA Repair

Helicases are specialised enzymes that translocate along DNA to unwind duplex structures, a fundamental step in replication, recombination and repair. Members of the RecQ family, notably the BLM helicase, maintain genome integrity by modulating stalled replication forks and processing DNA intermediates during homologous recombination. At sites of replication stress, helicases reverse or remodel fork structures to prevent collapse into double-strand breaks, thereby avoiding chromosomal rearrangements. During repair, they regulate strand invasion and disentanglement of recombination products, ensuring accurate lesion resolution. Dysregulation or mutation of helicases can lead to persistent DNA damage, chromosomal instability and accelerated cellular ageing, as seen in Bloom syndrome. Recent work has unveiled regulatory complexes and small-molecule modulators that influence helicase activity, opening avenues for targeted interventions in cancer therapy and radiosensitisation. This summary presents the latest mechanistic insights into helicase-mediated fork dynamics, their coordination with accessory factors and the consequences of helicase defects for human health.

Research from Nature Portfolio

Recent studies have uncovered a novel regulatory partnership between a GCFC domain-containing factor and the BLM helicase at stalled forks. This complex selectively binds fork-like DNA substrates, coordinating with RAD51 to promote fork reversal and preventing excessive helicase accumulation that otherwise sensitises cells to replication stress and fosters chromosomal instability.

Foundational genomic analyses have also assessed the prevalence of pathogenic germline mutations in the BLM gene among early-onset colorectal cancer patients. These investigations reveal a moderate enrichment of deleterious BLM variants in affected individuals, suggesting that heterozygous carriers carry an elevated, albeit incomplete-penetrance, risk of developing colorectal malignancies.

Helicase Function and Genomic Stability in DNA Repair publication trend

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

Technical terms

Helicase: An enzyme that separates duplex DNA into single strands using ATP hydrolysis, essential for replication and repair processes.

Replication fork reversal: A protective mechanism in which stalled replication forks are remodelled into four-way junctions to prevent collapse and facilitate repair.

Homologous recombination: An error-free DNA repair pathway that uses a homologous sequence as a template to accurately repair double-strand breaks.

Double-strand break: A form of DNA damage in which both strands of the helix are severed, posing a severe threat to genomic stability if unrepaired.

Genomic instability: The increased tendency for genome alterations, such as mutations, deletions or rearrangements, often arising from defective DNA repair.

References

1. TFIP11 promotes replication fork reversal to preserve genome stability. Nature Communications (2024).
2. Deleterious Germline BLM Mutations and the Risk for Early-onset Colorectal Cancer. Scientific Reports (2015).
3. Small molecules that disrupt RAD54-BLM interaction hamper tumor proliferation in colon cancer chemoresistance models. Journal of Clinical Investigation (2024).
4. RMI1 facilitates repair of ionizing radiation–induced DNA damage and maintenance of genomic stability. Cell Death Discovery (2023).
5. Bisbenzylisoquinoline alkaloid fangchinoline derivative HY-2 inhibits breast cancer cells by suppressing BLM DNA helicase. Biomedicine & Pharmacotherapy (2023).