Helicases: The Molecular Engines Powering Genome Stability

Helicases are essential nucleic-acid–processing enzymes that convert the chemical energy of ATP hydrolysis into mechanical force to unwind or remodel DNA and RNA structures. These molecular motors bind to duplex nucleic acids, translocate directionally along one strand, and separate complementary strands to enable key cellular processes such as DNA replication, transcription, recombination, repair, ribosome biogenesis, and RNA metabolism. Their activity depends on conserved motifs especially the Walker A and Walker B motifs that coordinate ATP binding and hydrolysis, while auxiliary domains determine substrate preference, polarity, and interactions with partner proteins. Helicases are classified into several superfamilies (SF1–SF6), each with distinct structural architectures and mechanistic signatures, ranging from inchworm-like movement to complex ring-shaped translocation mechanisms. Dysregulation or mutation of helicases is closely linked to genomic instability disorders, cancer predisposition, and impaired immune responses, highlighting their biomedical significance and their value as potential therapeutic targets.