What Is a DNA Helicase and How Does It Work?

DNA helicase is an enzyme that plays a part in accessing the genetic information stored within DNA. All organisms, from bacteria to humans, rely on these molecular machines. Their primary function is to unwind the tightly coiled, two-stranded DNA double helix. This action exposes the individual DNA strands, making the genetic code accessible for a variety of cellular activities. Without this unwinding process, the information in our genes would remain locked and unreadable.

The Mechanism of DNA Unwinding

DNA helicases function by breaking the hydrogen bonds that hold the two complementary strands of DNA together. This process requires energy, provided by the cell in the form of adenosine triphosphate (ATP). The helicase hydrolyzes ATP, a chemical reaction that releases energy. This energy is converted into mechanical force, allowing the helicase to move along the DNA and pry the two strands apart, much like a zipper unzipping a jacket.

This movement is directional and continuous, a property known as processivity. A single helicase enzyme can move along a DNA strand, unwinding thousands of base pairs without detaching. Different helicases have a specific directionality, traveling along a strand in either a 5′ to 3′ or a 3′ to 5′ direction. Many helicases assemble into a ring-shaped structure of six subunits that encircles a single DNA strand, which enhances their ability to stay attached and efficiently separate the strands.

The unwinding action creates a forked structure in the DNA known as a “replication fork,” which is the site where many DNA transactions begin. The helicase leads the way, preparing the DNA template for other enzymes to act upon the newly exposed genetic information.

Essential Roles in DNA Metabolism

Helicase activity is a prerequisite for DNA replication, the process of copying the genome before a cell divides. By unwinding the parental DNA, helicases create single-stranded templates necessary for DNA polymerase, the enzyme that synthesizes new DNA. At the start of replication, specialized proteins bind to specific locations on the DNA called origins, which then recruit helicases to begin unwinding. Two helicases are loaded, moving in opposite directions from the origin to create two replication forks.

DNA repair is another process that relies on helicase activity. When DNA is damaged by environmental factors or cellular metabolism, helicases are recruited to the site of the lesion. They unwind the DNA in the damaged region, providing access for repair enzymes to excise and replace the incorrect or damaged nucleotides. This function is important for maintaining the integrity of the genome and preventing mutations that could lead to disease.

Helicases also participate in genetic recombination, where segments of DNA are exchanged between chromosomes. This process requires unwinding DNA to allow for one DNA strand to invade another duplex, a step in creating genetic diversity and repairing certain DNA breaks. During transcription, the process of making an RNA copy of a gene, helicase activity is needed to unwind the DNA so that RNA polymerase can read the gene sequence.

Diversity and Classification of Helicases

The term “DNA helicase” refers not to a single enzyme, but to a broad and diverse class of motor proteins. Scientists classify these enzymes into six major groups, known as superfamilies (SF1 to SF6), based on the presence of specific, conserved amino acid sequences called motifs. These motifs are related to functions like ATP binding and hydrolysis, and their variations contribute to the specialized roles of different helicases.

This diversity is evident across different forms of life. While the basic function of unwinding DNA is conserved, the specific helicases found in bacteria differ in structure and complexity from those in eukaryotes, such as humans. For instance, the main replicative helicase in bacteria is a complex of six identical protein subunits, whereas in eukaryotes, it is formed from six different, though related, proteins.

Different helicases are also specialized for different tasks or substrates. Some are designed to unwind standard DNA-DNA double helices, while others can separate RNA-DNA hybrids formed during transcription. Certain helicases are tailored to act on specific DNA structures, such as G-quadruplexes, which can obstruct replication if not resolved.

Impact of Helicase Defects on Health

Because helicases are involved in many cellular processes, defects in these enzymes can have severe consequences for human health. Mutations in the genes that provide instructions for making helicase proteins can lead to genetic disorders known as “helicaseopathies.” These conditions are characterized by genomic instability, where the cell’s DNA is more prone to mutations and damage.

For example, Werner syndrome, caused by mutations in the WRN gene, leads to premature aging and an increased risk of cancer. Bloom syndrome results from defects in the BLM helicase and is associated with short stature, sun-sensitive skin rashes, and a high incidence of various cancers. Rothmund-Thomson syndrome is linked to mutations in the RECQL4 helicase and involves skin and skeletal abnormalities, along with an elevated cancer risk.

The symptoms seen in these disorders reflect the underlying failure of DNA replication and repair. When helicases do not function correctly, the genome cannot be copied or mended accurately. This leads to an accumulation of DNA damage, chromosomal abnormalities, and cellular dysfunction, which can manifest as accelerated aging and a predisposition to cancer.