DNAHelicase‐deficiency Disorders

Abstract

Deoxyribonucleic acid (DNA) helicases use energy derived from the hydrolysis of adenosine triphosphate (ATP) to separate the complementary strands of DNA. This article focuses on one family of DNA helicases , the human RECQ (recombination) helicases and the syndromes that arise due to their deficiency. The five human RECQ helicases share a common, conserved helicase domain and all five proteins appear to 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 the underlying genetics, biochemistry and function of the associated human RECQ helicase genes and proteins. 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 strands of duplex DNA molecules. RECQ helicases play important roles in many aspects of DNA metabolism including DNA replication and repair, recombination and telomere maintenance. Loss of RECQ helicase function is associated with defects in DNA metabolism, genetic instability, reduced cell proliferation and cellular senescence or apoptosis. Heritable human RECQ helicase deficiencies are rare. Three distinct autosomal recessive RECQ helicase deficiency syndromes have been identified thus far. RECQ helicase‐deficient individuals have an elevated risk of cancer together with additional developmental or acquired findings. Acquired RECQ helicase deficiencies may be common in adult cancer, where loss‐of‐function may modify the response to therapy.

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“…It must be noted that osteosarcoma is one of the human cancers with the highest frequency of alternative lenghtening of telomeres (36, 37), and indeed cancer is the leading cause of death in patients with germline RECQL4 mutations (32). Many of the pathogenic mutations that have been described involve the helicase and the PARP1 interaction domains, and usually spare the N-terminus (33). The interaction with PARP1 appears to play a role in RECQL4 localization to the nucleolus in response to oxidative stress (38).…”