DNA Helicase Deficiency Disorders

Abstract Deoxyribonucleic acid (DNA) helicases use energy derived from ATP (adenosine triphosphate) hydrolysis to separate the complementary strands of DNA. This article focuses on one family of DNA helicases, the human RECQ helicases, and the syndromes that arise in their absence or following loss of function. The five human RECQ helicases share a common, conserved helicase domain, and all five proteins play important roles in cellular DNA metabolism. Loss of function mutations in three family members cause the human cancer predisposition syndromes Bloom syndrome (BS), Werner syndrome (WS) and Rothmund–Thomson syndrome (RTS). This article outlines clinical features of the RECQ helicase deficiency syndromes, and reviews our understanding of the genetics, biochemistry and function of the syndrome‐associated RECQ helicases. We discuss how the loss of RECQ function may promote genetic instability and disease pathogenesis, and how RECQ helicases may serve as predictors of cancer risk and the response to therapy. Key Concepts RECQ helicases are found in all Kingdoms of life. RECQ helicases use the energy of ATP hydrolysis to unwind the two strands of DNA. RECQ helicases function in important aspects of DNA metabolism including DNA replication and repair, recombination, transcription and telomere maintenance. Loss of RECQ helicase function is associated with DNA metabolic defects, genetic instability, reduced cell proliferation and cellular senescence or apoptosis. Three rare, distinct heritable recessive human RECQ helicase deficiency syndromes have been identified. RECQ helicase‐deficient individuals have an elevated risk of cancer and additional developmental or acquired findings. Altered RECQ helicase function may be common in adult cancer, and may affect both cell viability and the response to therapy. RECQ‐specific inhibitors may be therapeutically useful in a subset of human cancers.