DNA Helicase‐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.

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 DC‐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 . 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.

close

References

Agrelo R, Cheng W‐H, Setien F et al. (2006) Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proceedings of the National Academy of Sciences of the USA 103(23): 8822–8827.

Ahn B, Harrigan JA, Indig FE et al. (2004) Regulation of WRN helicase activity in human base excision repair. Journal of Biological Chemistry 279(51): 53465–53474.

Baynton K, Otterlei M, Bjoras M et al. (2003) WRN interacts physically and functionally with the recombination mediator protein RAD52. Journal of Biological Chemistry 278(38): 36476–36486.

Bhattacharyya S, April S and Groden J (2009) Unwinding protein complexes in ALTernative telomere maintenance. Journal of Cellular Biochemistry 109(1): 7–15.

Bohr VA (2008) Rising from the RecQ‐age: the role of human RecQ helicases in genome maintenance. Trends in Biochemical Sciences 33(12): 609–620.

Bugreev DV, Mazina OM and Mazin AV (2009) Bloom syndrome helicase stimulates RAD51 DNA strand exchange activity through a novel mechanism. Journal of Biological Chemistry 284(39): 26349–26359.

Bugreev DV, Yu X, Egelman EH and Mazin AV (2008) Novel pro‐ and anti‐recombination activities of the Bloom's syndrome helicase. Genes & Development 21(23): 3085–3094.

Chakraborty P and Grosse F (2010) WRN helicase unwinds Okazaki fragment‐like hybrids in a reaction stimulated by the human DHX9 helicase. Nucleic Acids Research 38(14): 4722–4730.

Chan K‐L, North PS and Hickson ID (2007) BLM is required for faithful chromosome segregation and its localization defines a class of ultrafine anaphase bridges. EMBO Journal 26(14): 3397–3409.

Cheng W‐H, Muftic D, Muftuoglu M et al. (2008) WRN Is required for ATM activation and the S‐phase checkpoint in response to interstrand crosslink‐induced DNA double strand breaks. Molecular Biology of the Cell 19(9): 3922–3933.

Cheng W‐H, von Kobbe C, Opresko PL et al. (2004) Linkage between Werner Syndrome protein and the Mre11 complex via Nbs1. Journal of Biological Chemistry 279(20): 21169–21176.

Chu WK and Hickson ID (2009) RecQ helicases: multifunctional genome caretakers. Nature Reviews. Cancer 9(9): 644–654.

Crabbe L, Verdun RE, Haggblom CI and Karlseder J (2004) Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 306(5703): 1951–1953.

Davies SL, North PS, Dart A et al. (2004) Phosphorylation of the Bloom's syndrome helicase and Its role in recovery from S‐phase arrest. Molecular and Cellular Biology 24(3): 1279–1291.

Davies SL, North PS and Hickson ID (2007) Role for BLM in replication‐fork restart and suppression of origin firing after replicative stress. Nature Structural & Molecular Biology 14(7): 677–679.

Dhillon KK, Sidorova J, Saintigny Y et al. (2007) Functional role of the Werner syndrome RecQ helicase in human fibroblasts. Aging Cell 6(1): 53–61.

German J (1997) Bloom's syndrome. XX. The first 100 cancers. Cancer Genetics and Cytogenetics 93(1): 100–106.

Ghosh A, Rossi ML, Aulds J et al. (2009) Telomeric d‐loops containing 8‐oxo‐2′‐deoxyguanosine are preferred substrates for Werner and Bloom syndrome helicases and are bound by POT1. Journal of Biological Chemistry 284(45): 31074–31084.

Hoehn H, Bryant EM, Au K, Norwood TH et al. (1975) Variegated translocation mosaicism in human skin fibroblast cultures. Cytogenetics and Cell Genetics 15(5): 282–298.

Huang S, Lee L, Hanson NB et al. (2006) The spectrum of WRN mutations in Werner syndrome patients. Human Mutation 27(6): 558–567.

Kamath‐Loeb AS, Welcsh P, Waite M et al. (2004) The enzymatic activities of the Werner syndrome protein are disabled by the amino acid polymorphism R834C. Journal of Biological Chemistry 279(53): 55499–55505.

Kusumoto R, Dawut L, Marchetti C et al. (2008) Werner protein cooperates with the XRCC4‐DNA ligase IV complex in end‐processing. Biochemistry 47(28): 7548–7556.

Lebel M, Spillare EA, Harris CC and Leder P (1999) The Werner syndrome gene product co‐purifies with the DNA replication complex and interacts with PCNA and topoisomerase I. Journal of Biological Chemistry 274(53): 37795–37799.

Li B, Navarro S, Kasahara N and Comai L (2004) Identification and biochemical characterization of a Werner's syndrome protein complex with Ku70/80 and poly(ADP‐ribose) polymerase‐1. Journal of Biological Chemistry 279(14): 13659–13667.

Liu Y (2010) Rothmund‐Thomson syndrome helicase, RECQ4: on the crossroad between DNA replication and repair. DNA Repair 9(3): 325–330.

Maizels N (2006) Dynamic roles for G4 DNA in the biology of eukaryotic cells. Nature Structural & Molecular Biology 13(12): 1055–1059.

Mao FJ, Sidorova JM, Lauper JM et al. (2010) The human WRN and BLM RecQ helicases differentially regulate cell proliferation and survival after chemotherapeutic DNA damage. Cancer Research 70(16): 6548–6555.

Moser MJ, Bigbee WL, Grant SG et al. (2000a) Genetic instability and hematologic disease Risk in Werner syndrome patients and heterozygotes. Cancer Research 60(9): 2492–2496.

Moser MJ, Kamath‐Loeb AS, Jacob JE et al. (2000b) WRN helicase expression in Werner syndrome cell lines. Nucleic Acids Research 28(2): 648–654.

Opresko PL (2008) Telomere ResQue and preservation – roles for the Werner syndrome protein and other RecQ helicases. Mechanisms of Ageing and Development 129(1–2): 79–90.

Otterlei M, Bruheim P, Ahn B et al. (2006) Werner syndrome protein participates in a complex with RAD51, RAD54, RAD54B and ATR in response to ICL‐induced replication arrest. Journal of Cell Science 119(24): 5137–5146.

Ouyang KJ, Woo LL, Zhu J et al. (2009) SUMO modification regulates BLM and RAD51 interaction at damaged replication forks. PLoS Biology 7(12): e1000252.

Ozgenc A and Loeb LA (2005) Current advances in unraveling the function of the Werner syndrome protein. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 577(1–2): 237–251.

Pichierri P, Rosselli F and Franchitto A (2003) Werner's syndrome protein is phosphorylated in an ATR/ATM‐dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle. Oncogene 22(10): 1491–1500.

Plank JL, Wu J and Hsieh T‐S (2006) Topoisomerase IIIalpha and Bloom helicase can resolve a mobile double Holliday junction substrate through convergent branch migration. Proceedings of the National Academy of Sciences of the USA 103(30): 11118–11123.

Rao VA, Conti C, Guirouilh‐Barbat J et al. (2007) Endogenous {gamma}‐H2AX‐ATM‐Chk2 checkpoint activation in Bloom's syndrome helicase deficient cells is related to DNA replication arrested forks. Molecular Cancer Research 5(7): 713–724.

Rizzo A, Salvati E, Porru M et al. (2009) Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR‐dependent ATM signaling pathway. Nucleic Acids Research 37(16): 5353–5364.

Rossi ML, Ghosh AK and Bohr VA (2010) Roles of Werner syndrome protein in protection of genome integrity. DNA Repair 9(3): 331–344.

Saintigny Y, Makienko K, Swanson C et al. (2002) Homologous recombination resolution defect in Werner syndrome. Molecular and Cellular Biology 22(20): 6971–6978.

Salk D, Au K, Hoehn H and Martin GM (1981) Cytogenetics of Werner's syndrome cultured skin fibroblasts: variegated translocation mosaicism. Cytogenetics & Cell Genetics 30(2): 92–107.

Sfeir A, Kosiyatrakul ST, Hockemeyer D et al. (2009) Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell 138(1): 90–103.

Sharma S and Brosh RM Jr (2007) Human RECQL Is a DNA damage responsive protein required for genotoxic stress resistance and suppression of sister chromatid exchanges. PLoS ONE 2(12): e1297.

Sidorova JM (2008) Roles of the Werner syndrome RecQ helicase in DNA replication. DNA Repair 7: 1776–1786.

Sidorova JM, Li N, Folch A and Monnat RJ Jr (2008) The RecQ helicase WRN is required for normal replication fork progression after DNA damage or replication fork arrest. Cell Cycle 7(6): 796–807.

Siitonen HA, Sotkasiira J, Biervliet M et al. (2008) The mutation spectrum in RECQL4 diseases. European Journal of Human Genetics 17(2): 151–158.

Thangavel S, Mendoza‐Maldonado R, Tissino E et al. (2010) The human RECQL and RECQ4 helicases play distinct roles in DNA replication initiation. Molecular and Cellular Biology MCB.01290‐01209.

Vindigni A, Marino F and Gileadi O (2010) Probing the structural basis of RecQ helicase function. Biophysical Chemistry 149(3): 67–77.

Wang W (2007) Emergence of a DNA‐damage response network consisting of Fanconi anaemia and BRCA proteins. Nature Reviews. Genetics 8(10): 735–748.

Wu L (2008) Wrestling off RAD51: a novel role for RecQ helicases. BioEssays 30(4): 291–295.

Wu L, Davies SL, Levitt NC and Hickson ID (2001) Potential Role for the BLM helicase in recombinational repair via a conserved interaction with RAD51. Journal of Biological Chemistry 276(22): 19375–19381.

Wu L and Hickson ID (2003) The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 426(6968): 870–874.

Xu X, Rochette PJ, Feyissa EA et al. (2009) MCM10 mediates RECQ4 association with MCM2‐7 helicase complex during DNA replication. EMBO Journal 28(19): 3005–3014.

Further Reading

Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120(4): 513–522.

Crabbe L, Jauch A, Naeger CM et al. (2007) Telomere dysfunction as a cause of genomic instability in Werner syndrome. Proceedings of the National Academy of Sciences of the USA 104(7): 2205–2210.

Epstein CJ, Martin GM, Schultz AL and Motulsky AG (1966) Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore) 45(3): 177–221.

German J (1993) Bloom syndrome: a mendelian prototype of somatic mutational disease. Medicine (Baltimore) 72(6): 393–406.

Kudlow B, Kennedy BK and Monnat RJ Jr (2007) Werner and Hutchinson‐Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nature Reviews. Molecular Cell Biology 8: 394–404.

Ouyang KJ, Woo LL and Ellis NA (2008) Homologous recombination and maintenance of genome integrity: cancer and aging through the prism of human RecQ helicases. Mechanisms of Ageing and Development 129(7–8): 425–440.

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

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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]