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.

Keywords: RECQ helicases; Bloom syndrome; Werner syndrome; Rothmund–Thomson syndrome; DNA replication; DNA repair; telomeres; homologous recombination; genetic instability; cancer predisposition syndrome; premature ageing syndrome

Figure 1. Human RECQ helicase gene and protein family. The five human RECQ helicase proteins are shown as boxes (centre). Their official gene symbols and gene chromosomal locations are given to the left, and encoded catalytic activities to the right, of each protein diagram. All five proteins share a central, conserved RECQ helicase domain that encodes a 3′ to 5′ helicase activity. Four family members also contain RECQ consensus (RQC) domains, and three members a helicase and RNase D C‐terminal (HRDC) domain. Nuclear localisation signals (NLS) are depicted as short filled boxes. The 3′ to 5′ exonuclease domain is unique to WRN, whereas the Sld2 homology domain is found only in RECQL4.
Figure 2. RECQ substrates and DNA (deoxyribonucleic acid) metabolic roles. (a) The common model substrates on which RECQ helicases are active in vitro, and the pathways of DNA metabolism in which these substrates occur in vivo. RECQ helicases are able to unwind and release a flapped DNA strand, unwind nascent, that is short DNA strands in a fork, separate DNA duplexes joined in a Holiday junction and release an invading 3′ DNA tail in a D‐loop. WRN exonuclease can degrade the recessed 3′ end strand at DNA junctions in a fork and a D‐loop and blunt 3′ ends of duplex DNA if a DNA junction such as a HJ (or a regressed fork) is present. (b) Examples of more complex functions that can be performed by RECQ helicases, alone or in association with other proteins such as topoisomerase III alpha. A flag symbol on one of the DNA strands in a Holiday Junction and fork substrates marks a reference point to help visualise strand exchange between recombining duplexes or arms of a replication fork.
Figure 3. Model for the origins of human RECQ helicase deficiency syndromes. This model depicts cellular and organismal consequences of loss of RECQ helicase function during and after development. Loss of function in the RECQ helicase deficiency syndromes is constitutional and affects most or all cell lineages during and after development. Loss of function leads to genetic instability and cell loss by several mechanisms (see the text) that may compromise tissue or organ structure and function while promoting the emergence of cells with a proliferative advantage to form specific neoplasms. Some cell lineages may be particularly susceptible to genomic instability‐promoted tumourigenesis, for example the osteoblast (bone‐forming cell) lineage that gives rise to osteosarcomas in BS (Bloom syndrome) and WS (Werner syndrome) patients, and in RTS (Rothmund–Thomson syndrome) and RAPADILINO patients. Loss of WRN function also promotes cellular senescence, a nonspecific cancer suppressive mechanism that may restrict cancer outgrowth to a few susceptible cell lineages such as osteoblasts.
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Further Reading

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Oshima J, Hisama FM and Monnat RJ Jr (2017) Werner Syndrome as a model of human aging (Chapter 64). In: Michael Conn P (ed.) Handbook of Models of Human Aging, 2nd edn. Amsterdam: Elsevier Academic Press.

Wang LL, Levy ML, Lewis RA, et al. (2001) Clinical manifestations in a cohort of 41 Rothmund‐Thomson syndrome patients. American Journal of Medical Genetics 102 (1): 11–17.

Web Links

Bloom syndrome/BLM: https://www.ncbi.nlm.nih.gov/books/NBK1398

Rothmund–Thomson syndrome/RTS/RECQL4: https://www.ncbi.nlm.nih.gov/books/NBK1237

Werner syndrome/WRN: https://www.ncbi.nlm.nih.gov/books/NBK1514/

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Sidorova, Julia M, and Monnat Jr, Raymond J(Feb 2018) DNA Helicase Deficiency Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006065.pub3]