Helicase Functionality in DNA Repair Mechanisms

DNA helicases are ATP-dependent motor proteins that unwind duplex DNA and remodel nucleic acid structures, underpinning virtually all facets of genome maintenance. In response to DNA lesions such as double-strand breaks, interstrand crosslinks or stalled replication forks, helicases coordinate end resection, strand invasion, unwinding and re-annealing, often in concert with recombination proteins and single-strand binding factors. A subset of helicases exhibits dual activities, coupling canonical 3′–5′ translocation with intrinsic strand-annealing functions. Through regulated interactions with partners such as replication protein A, RAD51 and ATR kinase complexes, these enzymes ensure accurate repair by homologous recombination, single-strand annealing or microhomology-mediated end joining, thereby preventing mutagenesis and chromosome aberrations. Emerging evidence also implicates helicases in resolving RNA–DNA hybrids and interstrand crosslinks, highlighting their versatility in preserving genome integrity and their potential as targets for cancer therapeutics. Their malfunction is implicated in cancer predisposition, making helicases important both for understanding disease mechanisms and for developing novel therapeutic interventions.

Research from Nature Portfolio

Recent studies have illuminated how helicase HELQ employs co-factor-dependent switches between unwinding and strand-annealing to orchestrate double-strand break repair. Biochemical and single-molecule analyses reveal that RAD51 stimulates HELQ’s 3′–5′ translocation, promoting homologous recombination, whereas replication protein A inhibits unwinding while enhancing a secondary annealing activity that supports single-strand annealing pathways. Loss of HELQ impairs microhomology-mediated end joining and biases repair towards extended gene conversion tracts, underscoring its role in balancing pathway choice. Investigations into interstrand crosslink tolerance have uncovered a HELQ-dependent axis that operates alongside ATR kinase and RAD51 paralogues. Genetic disruption of HELQ sensitises cells to crosslinking agents and diminishes ATR-CHK1 signalling, while proteomic analyses identify stable interaction with RAD51B/C/D complexes. These findings position HELQ as a critical modulator of crosslink repair and checkpoint activation with implications for cancer susceptibility and chemotherapeutic resistance.

Helicase Functionality in DNA Repair Mechanisms publication trend

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

Technical terms

Helicase: An ATP-driven motor enzyme that separates duplex DNA into single strands.

Double-strand break (DSB): A lesion in which both strands of the DNA helix are severed.

Replication protein A (RPA): A heterotrimeric complex that binds single-stranded DNA to protect and stabilise it during repair.

RAD51: A recombinase that promotes strand invasion into a homologous DNA template during repair.

Single-strand annealing (SSA): A repair pathway that aligns and anneals homologous single-strand regions flanking a break, often deleting the intervening sequence.

Homologous recombination (HR): A high-fidelity repair process using a homologous DNA sequence as a template for accurate restoration.

Microhomology-mediated end joining (MMEJ): An error-prone repair route that uses short homologous sequences to join DNA ends, frequently causing small deletions.

Interstrand crosslink (ICL): A covalent bond linking opposite strands of DNA, blocking replication and transcription.

References

1. Interaction of human HelQ with DNA polymerase delta halts DNA synthesis and stimulates DNA single-strand annealing. Nucleic Acids Research (2023).
2. Helicase HELQ: Molecular Characters Fit for DSB Repair Function. International Journal of Molecular Sciences (2024).
3. HELQ is a dual-function DSB repair enzyme modulated by RPA and RAD51. Nature (2021).
4. Human DNA helicase HELQ participates in DNA interstrand crosslink tolerance with ATR and RAD51 paralogs. Nature Communications (2013).