DNA Helicase‐deficiency Disorders

Julia M Sidorova, University of Washington, Seattle, Washington, USA
Raymond J Monnat, University of Washington, Seattle, Washington, USA

Published online: November 2010

DOI: 10.1002/9780470015902.a0006065.pub2

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.

Keywords: RECQ helicases; Bloom syndrome; Werner syndrome; Rothmund–Thomson syndrome; DNA replication; DNA repair; telomeres; homologous recombination; genetic instability; cancer predisposition 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. Three family members also contain RECQ Consensus (RQC) domains, and two 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. Disease-causing mutations in human RECQ helicase genes. WRN, BLM and RECQL4 open reading frames are depicted as boxes with domains indicated as in Figure 1. Two additional acidic domains are shown for WRN: the acidic repeat domain (acidic) and a short hyperacidic (ha) stretch consisting of aspartic and glutamic acid residues preceding the helicase domain. Residue and mRNA base pair coordinates beginning with the ‘A’ of the ATG start codon as bp 1 are shown to the left of the each protein. Coding region nonsynonymous SNP polymorphisms are shown above, and clinically ascertained mutations below, each RECQ protein. Mutations, not consequences, are shown; and only single symbols for specific mutations observed in one or more patients. The WRN R834C SNP polymorphism is circled (see text), and large WRN deletions and a duplication are indicated by a horizontal line linked to the appropriate type symbol. RECQL4 mutations identified in Rothmund–Thmonson, RAPADILINO or Baller–Gerold syndrome patients are further indicated by the symbol fill, with the key to the lower right.
Figure 3. RECQ substrates and DNA 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, short DNA strands in a fork, separate DNA duplexes joined in a Holliday 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 IIIalpha. A flag symbol on one of the DNA strands in a Holliday Junction and fork substrates marks a reference point to help visualise strand exchange between recombining duplexes or arms of a replication fork.
Figure 4. 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 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 tumorigenesis, for example the osteoblast (bone-forming cell) lineage that gives rise to osteosarcomas in BS and WS patients, and in RTS and RAPADILINO patients. Loss of WRN function also promotes cellular senescence, and thus may provide a nonspecific tumour suppressive mechanism that limits tumour formation to a few susceptible cell lineages such as osteoblasts.
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 Web links
 Bloom syndrome/BLM
    ePath Entrez Gene record with Reference Sequence (RefSeq) gene and protein links: http://www.ncbi.nlm.nih.gov/gene/641
    ePath GeneClinics Gene Review: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=bloom
    ePath On-line Mendelian Inheritance in Man (OMIM) record: http://www.ncbi.nlm.nih.gov/omim/210900
 Werner syndrome/WRN
    ePath Entrez Gene record with Reference Sequence (RefSeq) gene and protein links: http://www.ncbi.nlm.nih.gov/gene/7486
    ePath GeneClinics Gene Review: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=werner
    ePath International Registry of Werner Syndrome: http://www.pathology.washington.edu/research/werner/registry/registry.html
    ePath On-line Mendelian Inheritance in Man (OMIM) record: http://www.ncbi.nlm.nih.gov/omim/277700
    ePath Werner Syndrome Locus-specific Mutation Database: http://www.pathology.washington.edu/research/werner/database/
 Rothmund-Thomson syndrome/RTS
    ePath Entrez Gene record with Reference Sequence (RefSeq) gene and protein links: http://www.ncbi.nlm.nih.gov/gene/9401
    ePath GeneClinics Gene Review: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=rts
    ePath On-line Mendelian Inheritance in Man (OMIM) record: http://www.ncbi.nlm.nih.gov/omim/268400
 RAPADILINO syndrome
    ePath On-line Mendelian Inheritance in Man (OMIM) record: http://www.ncbi.nlm.nih.gov/omim/266280
 Baller-Gerold syndrome
    ePath GeneClinics Gene Review: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=bgs
    ePath On-line Mendelian Inheritance in Man (OMIM) record: http://www.ncbi.nlm.nih.gov/omim/218600
 RECQL/RECQL1
    ePath Entrez Gene record with Reference Sequence (RefSeq) gene and protein links: http://www.ncbi.nlm.nih.gov/gene/5965
 RECQL5
    ePath Entrez Gene record with Reference Sequence (RefSeq) gene and protein links: http://www.ncbi.nlm.nih.gov/gene/9400

Related Sub-Topics:

Nucleic Acid Structure | Replication and Recombination | Transcription | Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Biomolecular Interactions | Enzymes: Structure and Action Mechanism | Nucleic Acids: Structure, Function, Metabolism
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Article Title: DNA Helicase‐deficiency Disorders
 
How to Cite close
Sidorova, Julia M, and Monnat, Raymond J(Nov 2010) DNA Helicase‐deficiency Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006065.pub2]