DNA Helicase Deficiency Disorders


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.


Aygun O, Svejstrup J and Liu Y (2008) A RECQ5‐RNA polymerase II association identified by targeted proteomic analysis of human chromatin. Proceedings of the National Academy of Sciences of the United States of America 105: 8580–8584.

Basile G, Leuzzi G, Pichierri P and Franchitto A (2014) Checkpoint‐dependent and independent roles of the Werner syndrome protein in preserving genome integrity in response to mild replication stress. Nucleic Acids Research 42: 12628–12639.

Berti M, Chaudhuri AR, Thangavel S, et al. (2013) Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nature Structural & Molecular Biology 2013: 2501.

Berti M and Vindigni A (2016) Replication stress: getting back on track. Nature Structural & Molecular Biology 23: 103–109.

Böhm S and Bernstein KA (2014) The role of post‐translational modifications in fine‐tuning BLM helicase function during DNA repair. DNA Repair 22: 123–132.

Bosch LJ, Luo Y, Lao VV, et al. (2016) WRN promoter CpG island hypermethylation does not predict more favorable outcomes for patients with metastatic colorectal cancer treated with irinotecan‐based therapy. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research 22: 4612–4622.

Brambati A, Colosio A, Zardoni L, Galanti L and Liberi G (2015) Replication and transcription on a collision course: eukaryotic regulation mechanisms and implications for DNA stability. Frontiers in Genetics 6: 166.

Budhathoki JB, Stafford EJ, Yodh JG and Balci H (2015) ATP‐dependent G‐quadruplex unfolding by Bloom helicase exhibits low processivity. Nucleic Acids Research 43: 5961–5970.

Budhathoki JB, Maleki P, Roy WA, et al. (2016) A comparative study of G‐Quadruplex unfolding and DNA reeling activities of human RECQ5 helicase. Biophysical Journal 110: 2585–2596.

Chabosseau P, Buhagiar‐Labarchede G, Onclercq‐Delic R, et al. (2011) Pyrimidine pool imbalance induced by BLM helicase deficiency contributes to genetic instability in Bloom syndrome. Nature Communications 2: 368.

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: 3397–3409.

Chang EY, Novoa CA, Aristizabal MJ, et al. (2017) RECQ‐like helicases Sgs1 and BLM regulate R‐loop‐associated genome instability. Journal of Cell Biology 216 (12): 3991–4005.

Croteau DL, Popuri V, Opresko PL and Bohr VA (2014) Human RecQ helicases in DNA repair, recombination, and replication. Annual Review of Biochemistry 83: 519–552.

Drosopoulos WC, Kosiyatrakul ST and Schildkraut CL (2015) BLM helicase facilitates telomere replication during leading strand synthesis of telomeres. The Journal of Cell Biology 210: 191–208.

Fu W, Ligabue A, Rogers KJ, Akey JM and Monnat RJ Jr (2017) Human RECQ helicase pathogenic variants, population variation and “missing” diseases. Human Mutation 38: 193–203.

Ghosh A, Rossi ML, Aulds J, Croteau D and Bohr VA (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: 31074–31084.

Grundy GJ, Rulten SL, Arribas‐Bosacoma R, et al. (2016) The Ku‐binding motif is a conserved module for recruitment and stimulation of non‐homologous end‐joining proteins. Nature Communications 7: 11242.

Higa M, Fujita M and Yoshida K (2017) DNA replication origins and fork progression at mammalian telomeres. Genes (Basel) 8. pii: E112.

Hu Y, Lu X, Barnes E, et al. (2005) Recql5 and Blm RecQ DNA helicases have nonredundant roles in suppressing crossovers. Molecular and Cellular Biology 25: 3431–3442.

Hu Y, Raynard S, Sehorn MG, et al. (2007) RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments. Genes & Development 21: 3073–3084.

Kamath‐Loeb AS, Loeb LA, Johansson E, Burgers PMJ and Fry M (2001) Interactions between the Werner Syndrome Helicase and DNA polymerase delta specifically facilitate copying of tetraplex and hairpin structures of the d(CGG)n trinucleotide repeat sequence. Journal of Biological Chemistry 276: 16439–16446.

Kamath‐Loeb AS, Welcsh P, Waite M, Adman ET and Loeb LA (2004) The enzymatic activities of the Werner Syndrome Protein are disabled by the amino acid polymorphism R834C. The Journal of Biological Chemistry 279: 55499–55505. Epub 2004 Oct 15.

Kamath‐Loeb AS, Lan L, Nakajima S, Yasui A and Loeb LA (2007) Werner syndrome protein interacts functionally with translesion DNA polymerases. Proceedings of the National Academy of Sciences 104: 10394–10399.

Keijzers G, Maynard S, Shamanna RA, et al. (2014) The role of RecQ helicases in non‐homologous end‐joining. Critical Reviews in Biochemistry and Molecular Biology 49 (6): 463–472.

Khadka P, Croteau DL and Bohr VA (2016) RECQL5 has unique strand annealing properties relative to the other human RecQ helicase proteins. DNA Repair (Amst) 37: 53–66.

Klaue D, Kobbe D, Kemmerich F, et al. (2013) Fork sensing and strand switching control antagonistic activities of RecQ helicases. Nature Communications 4: 2024.

Kwok CK and Merrick CJ (2017) G‐quadruplexes: prediction, characterization, and biological application. Trends in Biotechnology 35: 997–1013.

Lao VV, Welcsh P, Luo Y, et al. (2013) Altered RECQ helicase expression in sporadic primary colorectal cancers. Translational Oncology 6: 458–469.

Li M, Xu X and Liu Y (2011) The SET2‐RPB1 interaction domain of human RECQ5 is important for transcription‐associated genome stability. Molecular and Cellular Biology 31: 2090–2099.

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

Lu X, Parvathaneni S, Hara T, Lal A and Sharma S (2013) Replication stress induces specific enrichment of RECQ1 at common fragile sites FRA3B and FRA16D. Molecular Cancer 12: 29.

Lu H, Shamanna RA, Keijzers G, et al. (2016) RECQL4 promotes DNA end resection in repair of DNA double‐strand breaks. Cell Reports 16: 161–173.

Manthei KA and Keck JL (2013) The BLM dissolvasome in DNA replication and repair. Cellular and Molecular Life Sciences: CMLS 70: 4067–4084.

Mendez‐Bermudez A, Hidalgo‐Bravo A, Cotton VE, et al. (2012) The roles of WRN and BLM RecQ helicases in the alternative lengthening of telomeres. Nucleic Acids Research 40: 10809–10820.

Mendoza O, Bourdoncle A, Boule JB, Brosh RM Jr and Mergny JL (2016) G‐quadruplexes and helicases. Nucleic Acids Research 44: 1989–2006.

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

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

Neelsen KJ and Lopes M (2015) Replication fork reversal in eukaryotes: from dead end to dynamic response. Nature Reviews. Molecular Cell Biology 16: 207–220.

Nguyen GH, Tang W, Robles AI, et al. (2014) Regulation of gene expression by the BLM helicase correlates with the presence of G‐quadruplex DNA motifs. Proceedings of the National Academy of Sciences of the United States of America 111: 9905–9910.

Opresko PL and Shay JW (2017) Telomere‐associated aging disorders. Ageing Research Reviews 33: 52–66.

Oshima J, Sidorova JM and Monnat RJ (2017) Werner syndrome: clinical features, pathogenesis and potential therapeutic interventions. Ageing Research Reviews 33: 105–114.

Ozeri‐Galai E, Tur‐Sinai M, Bester AC and Kerem B (2014) Interplay between genetic and epigenetic factors governs common fragile site instability in cancer. Cellular and Molecular Life Sciences 71: 4495–4506.

Papadopoulou C, Guilbaud G, Schiavone D and Sale JE (2015) Nucleotide pool depletion induces G‐quadruplex‐dependent perturbation of gene expression. Cell Reports 13: 2491–2503.

Parvathaneni S, Stortchevoi A, Sommers JA, Brosh RM Jr and Sharma S (2013) Human RECQ1 interacts with Ku70/80 and modulates DNA end‐joining of double‐strand breaks. PLoS One 8: e62481.

Pichierri P, Ammazzalorso F, Bignami M and Franchitto A (2011) The Werner syndrome protein: linking the replication checkpoint response to genome stability. Aging 3: 311–318.

Popuri V, Bachrati CZ, Muzzolini L, et al. (2008) The human RecQ helicases, BLM and RECQ1, display distinct DNA substrate specificities. The Journal of Biological Chemistry 283: 17766–17776.

Popuri V, Croteau DL, Brosh RM Jr and Bohr VA (2012) RECQ1 is required for cellular resistance to replication stress and catalyzes strand exchange on stalled replication fork structures. Cell Cycle 11: 4252–4265.

Popuri V, Huang J, Ramamoorthy M, et al. (2013) RECQL5 plays co‐operative and complementary roles with WRN syndrome helicase. Nucleic Acids Research 41: 881–899.

Popuri V, Hsu J, Khadka P, et al. (2014) Human RECQL1 participates in telomere maintenance. Nucleic Acids Research 42: 5671–5688.

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

Saintigny Y, Makienko K, Swanson C, Emond MJ and Monnat RJ Jr (2002) Homologous recombination resolution defect in Werner syndrome. Molecular and Cellular Biology 22: 6971–6978.

Sami F and Sharma S (2013) Probing genome maintenance functions of human RECQ1. Computational and Structural Biotechnology Journal 6: e201303014.

Sarkies P, Murat P, Phillips LG, et al. (2012) FANCJ coordinates two pathways that maintain epigenetic stability at G‐quadruplex DNA. Nucleic Acids Research 40: 1485–1498.

Shamanna RA, Lu H, de Freitas JK, et al. (2016) WRN regulates pathway choice between classical and alternative non‐homologous end joining. Nature Communications 7: 13785.

Sharma S and Brosh RM Jr (2007) Human RECQ1 Is a DNA damage responsive protein required for genotoxic stress resistance and suppression of sister chromatid exchanges. PLoS One 2: e1297.

Shin S, Lee J, Yoo S, et al. (2016) Active control of repetitive structural transitions between replication forks and holliday junctions by Werner syndrome helicase. Structure (London, England: 1993) 24: 1292–1300.

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

Singh DK, Popuri V, Kulikowicz T, et al. (2012) The human RecQ helicases BLM and RECQL4 cooperate to preserve genome stability. Nucleic Acids Research 40: 6632–6648.

Sturzenegger A, Burdova K, Kanagaraj R, et al. (2014) DNA2 cooperates with the WRN and BLM RecQ helicases to mediate long‐range DNA‐end resection in human cells. The Journal of Biological Chemistry 289 (39): 27314–27326.

Swuec P and Costa A (2014) Molecular mechanism of double Holliday junction dissolution. Cell & Bioscience 4: 36.

Tang W, Robles AI, Beyer RP, et al. (2016) The Werner syndrome RECQ helicase targets G4 DNA in human cells to modulate transcription. Human Molecular Genetics 25: 2060–2069.

Thangavel S, Mendoza‐Maldonado R, Tissino E, et al. (2010) The human RECQ1 and RECQ4 helicases play distinct roles in DNA replication initiation. Molecular and Cellular Biology: MCB 30 (6): 1382–1396.

Thangavel S, Berti M, Levikova M, et al. (2015) DNA2 drives processing and restart of reversed replication forks in human cells. Journal of Cell Biology 208: 545–562.

Tokita M, Kennedy SR, Risques RA, et al. (2016) Werner syndrome through the lens of tissue and tumour genomics. Scientific Reports 6: 32038.

Urban V, Dobrovolna J, Huhn D, et al. (2016) RECQ5 helicase promotes resolution of conflicts between replication and transcription in human cells. Journal of Cell Biology 214: 401–415.

Urban V, Dobrovolna J and Janscak P (2017) Distinct functions of human RecQ helicases during DNA replication. Biophysical Chemistry 225: 20–26.

Welcsh P, Kehrli K, Lazarchuk P, Ladiges W and Sidorova J (2016) Application of the microfluidic‐assisted replication track analysis to measure DNA repair in human and mouse cells. Methods 108: 99–110.

Yodh JG, Stevens BC, Kanagaraj R, Janscak P and Ha T (2009) BLM helicase measures DNA unwound before switching strands and hRPA promotes unwinding reinitiation. EMBO Journal 28: 405–416.

Further Reading

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.

Cunniff C, Bassetti JA and Ellis NA (2017) Bloom's syndrome: clinical spectrum, molecular pathogenesis, and cancer predisposition. Molecular Syndromology 8 (1): 4–23. DOI: 10.1159/000452082.

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

Larizza L, Roversi G and Volpi L (2010) Rothmund‐Thomson syndrome. Orphanet Journal of Rare Diseases 5: 2. DOI: 10.1186/1750-1172-5-2. PMID: 20113479.

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]