DNA Helicase Function and Genome Integrity

DNA helicases are motor proteins that translocate along nucleic acids to separate complementary strands, a step essential for replication, repair and recombination. By unwinding duplex DNA and resolving secondary structures such as G-quadruplexes and R-loops, helicases safeguard the progression of replication forks and the accurate transmission of genetic information. Dysfunction or misregulation of helicase activity can compromise genome integrity, leading to replication stress, chromosomal aberrations and susceptibility to disease. Recent work has revealed mechanistic insights into how helicases are recruited to stalled replisomes, how they collaborate with accessory factors to negotiate complex DNA structures and how their activity is modulated in response to metabolic and environmental cues. Advances in structural biology and single-molecule techniques have begun to elucidate the conformational changes that drive helicase translocation and the specific interactions that govern substrate recognition. Decoding these mechanisms provides a foundation for therapeutic strategies that target helicases in cancer and ageing, where genome instability plays a pivotal role.

Research from Nature Portfolio

A structural study of the Pif1 helicase complexed with a G-quadruplex DNA has defined a conserved “wedge” motif in the 1A domain that engages the G-tetrad and initiates unfolding. This work demonstrates that the same structural element mediates duplex and G-quadruplex unwinding, explaining how Pif1 preserves replication fork progression across guanine-rich regions. A second investigation into the yeast rrm3 mutant under caloric restriction has uncovered a Sir-complex-dependent increase in cell death linked to stalled replication at natural pause sites. These findings implicate metabolic state in helicase-mediated genome maintenance and suggest new angles for adjuvant therapies. Finally, a foundational contribution delineated how Pif1 and Rrm3 collaborate to displace R-loops at tRNA genes, establishing a mechanism by which helicases remove persistent RNA–DNA hybrids to prevent transcription-associated DNA damage.

DNA Helicase Function and Genome Integrity publication trend

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

Technical terms

DNA helicase: An enzyme that unwinds double-stranded DNA into single strands, powered by ATP hydrolysis.

Replication fork: The Y-shaped region where parental DNA is being unwound and replicated during cell division.

G-quadruplex: A four-stranded DNA secondary structure formed by guanine-rich sequences that can impede replication.

R-loop: A three-strand nucleic acid structure consisting of an RNA–DNA hybrid and displaced single-stranded DNA, which can cause genome instability.

Replisome: The multi-protein complex responsible for DNA synthesis and processing at replication forks.

References

1. Eukaryotic Pif1 helicase unwinds G-quadruplex and dsDNA using a conserved wedge. Nature Communications (2024).
2. The increase in cell death rates in caloric restricted cells of the yeast helicase mutant rrm3 is Sir complex dependent. Scientific Reports (2023).
3. PIF1 family DNA helicases suppress R-loop mediated genome instability at tRNA genes. Nature Communications (2017).
4. Rrm3 and Pif1 division of labor during replication through leading and lagging strand G-quadruplex. Nucleic Acids Research (2023).
5. A common mechanism for recruiting the Rrm3 and RTEL1 accessory helicases to the eukaryotic replisome. The EMBO Journal (2024).
6. The functional significance of the RPA- and PCNA-dependent recruitment of Pif1 to DNA. EMBO Reports (2024).