Home LiteratureArticle Details
PMID: 19949442 Published · ppublish English Journal Article

RecQ helicases: multiple structures for multiple functions?

HFSP journal ·Vol. 3 ·No. 3 ·2009-06-00 ·Pages 153-64

Vindigni A, Hickson ID

Abstract

Approximately 1% of the open reading frames in the human genome encode proteins that function as DNA or RNA helicases. These enzymes act in all aspects of nucleic acid metabolism where the complementary strands of DNA:DNA or DNA:RNA duplexes require to be transiently opened. However, they perform wider roles in nucleic acid metabolism due to their ability to couple the energy derived from hydrolysis of ATP to their unidirectional translocation along strands of DNARNA. In this way, helicases can displace proteins from DNARNA, drive the migration of DNA junctions (such as the Holliday junction recombination intermediate), or generate superhelical tension in nucleic acid duplexes. Here, we review a subgroup of DNA helicase enzymes, the RecQ family, that has attracted considerable interest in recent years due to their role not only in suppression of genome instability, but also in the avoidance of human disease. We focus particularly on the protein structural motifs and the multiple assembly states that characterize RecQ helicases and discuss novel biophysical techniques to study the different RecQ structures present in solution. We also speculate on the roles of the different domains and oligomeric forms in defining which DNA structures will represent substrates for RecQ helicase-mediated transactions.

Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Vindigni Alessandro
Hickson Ian D
References (114)
114 references, click to expand
  1. Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51.
    J Biol Chem. 2001 Jun 1;276(22):19375-81 PMID: 11278509
  2. Solution structure of a multifunctional DNA- and protein-binding motif of human Werner syndrome protein.
    Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18379-84 PMID: 16339893
  3. Oligomeric ring structure of the Bloom's syndrome helicase.
    Curr Biol. 1999 Jun 3;9(11):597-600 PMID: 10359700
  4. Werner syndrome protein. I. DNA helicase and dna exonuclease reside on the same polypeptide.
    J Biol Chem. 1998 Dec 18;273(51):34139-44 PMID: 9852073
  5. The Bloom's syndrome helicase promotes the annealing of complementary single-stranded DNA.
    Nucleic Acids Res. 2005 Jul 15;33(12):3932-41 PMID: 16024743
  6. RMI, a new OB-fold complex essential for Bloom syndrome protein to maintain genome stability.
    Genes Dev. 2008 Oct 15;22(20):2843-55 PMID: 18923082
  7. A conserved G4 DNA binding domain in RecQ family helicases.
    J Mol Biol. 2006 May 12;358(4):1071-80 PMID: 16530788
  8. Non-hexameric DNA helicases and translocases: mechanisms and regulation.
    Nat Rev Mol Cell Biol. 2008 May;9(5):391-401 PMID: 18414490
  9. A double Holliday junction dissolvasome comprising BLM, topoisomerase IIIalpha, and BLAP75.
    J Biol Chem. 2006 May 19;281(20):13861-4 PMID: 16595695
  10. Structural basis for the cooperative assembly of large T antigen on the origin of replication.
    J Mol Biol. 2006 Apr 7;357(4):1295-305 PMID: 16481006
  11. Junction of RecQ helicase biochemistry and human disease.
    J Biol Chem. 2004 Apr 30;279(18):18099-102 PMID: 15023996
  12. The Bloom's syndrome helicase unwinds G4 DNA.
    J Biol Chem. 1998 Oct 16;273(42):27587-92 PMID: 9765292
  13. Structure and function of the regulatory C-terminal HRDC domain from Deinococcus radiodurans RecQ.
    Nucleic Acids Res. 2008 May;36(9):3139-49 PMID: 18411208
  14. Structure of the winged-helix protein hRFX1 reveals a new mode of DNA binding.
    Nature. 2000 Feb 24;403(6772):916-21 PMID: 10706293
  15. Helicases become mechanistically simpler and functionally more complex.
    Nat Struct Mol Biol. 2004 Jun;11(6):494-6 PMID: 15164003
  16. RecQ helicases: guardian angels of the DNA replication fork.
    Chromosoma. 2008 Jun;117(3):219-33 PMID: 18188578
  17. Structure and function of RecQ DNA helicases.
    Crit Rev Biochem Mol Biol. 2004 Mar-Apr;39(2):79-97 PMID: 15217989
  18. Global conformation of the Escherichia coli replication factor DnaC protein in absence and presence of nucleotide cofactors.
    Biochemistry. 2004 Aug 31;43(34):10988-1001 PMID: 15323558
  19. Association of the Bloom syndrome protein with topoisomerase IIIalpha in somatic and meiotic cells.
    Cancer Res. 2000 Mar 1;60(5):1162-7 PMID: 10728666
  20. Crystal structure of the HRDC domain of human Werner syndrome protein, WRN.
    J Biol Chem. 2007 Jan 26;282(4):2717-28 PMID: 17148451
  21. Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity.
    J Biol Chem. 2000 Aug 4;275(31):23500-8 PMID: 10825162
  22. Werner's syndrome protein (WRN) migrates Holliday junctions and co-localizes with RPA upon replication arrest.
    EMBO Rep. 2000 Jul;1(1):80-4 PMID: 11256630
  23. Positionally cloned human disease genes: patterns of evolutionary conservation and functional motifs.
    Proc Natl Acad Sci U S A. 1997 May 27;94(11):5831-6 PMID: 9159160
  24. Human homologues of yeast helicase.
    Nature. 1996 Oct 24;383(6602):678-9 PMID: 8878475
  25. High-resolution structure of the E.coli RecQ helicase catalytic core.
    EMBO J. 2003 Oct 1;22(19):4910-21 PMID: 14517231
  26. Functional and physical interaction between WRN helicase and human replication protein A.
    J Biol Chem. 1999 Jun 25;274(26):18341-50 PMID: 10373438
  27. MPS1-dependent mitotic BLM phosphorylation is important for chromosome stability.
    Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11485-90 PMID: 16864798
  28. Structural insight of human DEAD-box protein rck/p54 into its substrate recognition with conformational changes.
    Genes Cells. 2006 Apr;11(4):439-52 PMID: 16611246
  29. Werner syndrome protein is regulated and phosphorylated by DNA-dependent protein kinase.
    J Biol Chem. 2001 Oct 12;276(41):38242-8 PMID: 11477099
  30. Quaternary structure and catalytic activity of the Escherichia coli ribonuclease E amino-terminal catalytic domain.
    Biochemistry. 2003 Dec 2;42(47):13848-55 PMID: 14636052
  31. Characterization of the human and mouse WRN 3'-->5' exonuclease.
    Nucleic Acids Res. 2000 Jun 15;28(12):2396-405 PMID: 10871373
  32. Domain mapping of Escherichia coli RecQ defines the roles of conserved N- and C-terminal regions in the RecQ family.
    Nucleic Acids Res. 2003 Jun 1;31(11):2778-85 PMID: 12771204
  33. RecQ helicases: caretakers of the genome.
    Nat Rev Cancer. 2003 Mar;3(3):169-78 PMID: 12612652
  34. WRN exonuclease structure and molecular mechanism imply an editing role in DNA end processing.
    Nat Struct Mol Biol. 2006 May;13(5):414-22 PMID: 16622405
  35. A RECQ5-RNA polymerase II association identified by targeted proteomic analysis of human chromatin.
    Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8580-4 PMID: 18562274
  36. Molecular genetics of RecQ helicase disorders.
    Cell Mol Life Sci. 2007 Sep;64(17):2306-22 PMID: 17571213
  37. Structure of the human RECQ1 helicase reveals a putative strand-separation pin.
    Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1039-44 PMID: 19151156
  38. Biochemical analysis of the DNA unwinding and strand annealing activities catalyzed by human RECQ1.
    J Biol Chem. 2005 Jul 29;280(30):28072-84 PMID: 15899892
  39. The three-dimensional structure of the HRDC domain and implications for the Werner and Bloom syndrome proteins.
    Structure. 1999 Dec 15;7(12):1557-66 PMID: 10647186
  40. Human RECQ5beta, a protein with DNA helicase and strand-annealing activities in a single polypeptide.
    EMBO J. 2004 Jul 21;23(14):2882-91 PMID: 15241474
  41. Three HRDC domains differentially modulate Deinococcus radiodurans RecQ DNA helicase biochemical activity.
    J Biol Chem. 2006 May 5;281(18):12849-57 PMID: 16531400
  42. Werner protein is a target of DNA-dependent protein kinase in vivo and in vitro, and its catalytic activities are regulated by phosphorylation.
    J Biol Chem. 2002 May 24;277(21):18291-302 PMID: 11889123
  43. Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability.
    Hum Mol Genet. 2001 Jun 1;10(12):1287-98 PMID: 11406610
  44. Pathways and functions of the Werner syndrome protein.
    Mech Ageing Dev. 2005 Jan;126(1):79-86 PMID: 15610765
  45. Substrate-specific inhibition of RecQ helicase.
    Nucleic Acids Res. 2001 Apr 15;29(8):1765-71 PMID: 11292849
  46. Characterization and mutational analysis of the RecQ core of the bloom syndrome protein.
    J Mol Biol. 2003 Jun 27;330(1):29-42 PMID: 12818200
  47. The Bloom's syndrome helicase (BLM) interacts physically and functionally with p12, the smallest subunit of human DNA polymerase delta.
    Nucleic Acids Res. 2008 Sep;36(16):5166-79 PMID: 18682526
  48. Crystal structures of complexes of PcrA DNA helicase with a DNA substrate indicate an inchworm mechanism.
    Cell. 1999 Apr 2;97(1):75-84 PMID: 10199404
  49. Isolation and genetic characterization of a thymineless death-resistant mutant of Escherichia coli K12: identification of a new mutation (recQ1) that blocks the RecF recombination pathway.
    Mol Gen Genet. 1984;195(3):474-80 PMID: 6381965
  50. The Bloom's syndrome gene product is homologous to RecQ helicases.
    Cell. 1995 Nov 17;83(4):655-66 PMID: 7585968
  51. Werner syndrome protein contains three structure-specific DNA binding domains.
    J Biol Chem. 2003 Dec 26;278(52):52997-3006 PMID: 14534320
  52. The Human RecQ helicases, BLM and RECQ1, display distinct DNA substrate specificities.
    J Biol Chem. 2008 Jun 27;283(26):17766-76 PMID: 18448429
  53. Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases.
    Hum Mol Genet. 2003 Nov 1;12(21):2837-44 PMID: 12952869
  54. Biochemical characterization of the RECQ4 protein, mutated in Rothmund-Thomson syndrome.
    DNA Repair (Amst). 2006 Feb 3;5(2):172-80 PMID: 16214424
  55. Genome stability and the processing of damaged replication forks by RecG.
    Trends Genet. 2002 Aug;18(8):413-9 PMID: 12142010
  56. Analysis of the unwinding activity of the dimeric RECQ1 helicase in the presence of human replication protein A.
    Nucleic Acids Res. 2004 Apr 19;32(7):2158-70 PMID: 15096578
  57. Crystal structure of a CAP-DNA complex: the DNA is bent by 90 degrees.
    Science. 1991 Aug 30;253(5023):1001-7 PMID: 1653449
  58. 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. 2003 Mar 13;22(10):1491-500 PMID: 12629512
  59. The zinc finger motif of Escherichia coli RecQ is implicated in both DNA binding and protein folding.
    J Biol Chem. 2004 Oct 8;279(41):42794-802 PMID: 15292213
  60. Coordinate action of the helicase and 3' to 5' exonuclease of Werner syndrome protein.
    J Biol Chem. 2001 Nov 30;276(48):44677-87 PMID: 11572872
  61. Biochemical characterization of the DNA helicase activity of the escherichia coli RecQ helicase.
    J Biol Chem. 2001 Jan 5;276(1):232-43 PMID: 11024023
  62. POLQ (Pol theta), a DNA polymerase and DNA-dependent ATPase in human cells.
    Nucleic Acids Res. 2003 Nov 1;31(21):6117-26 PMID: 14576298
  63. Rising from the RecQ-age: the role of human RecQ helicases in genome maintenance.
    Trends Biochem Sci. 2008 Dec;33(12):609-20 PMID: 18926708
  64. Purification and characterization of the Sgs1 DNA helicase activity of Saccharomyces cerevisiae.
    J Biol Chem. 1998 Apr 17;273(16):9644-50 PMID: 9545297
  65. Expression of a RecQ helicase homolog affects progression through crisis in fission yeast lacking telomerase.
    J Biol Chem. 2005 Feb 18;280(7):5249-57 PMID: 15591066
  66. The galvanization of biology: a growing appreciation for the roles of zinc.
    Science. 1996 Feb 23;271(5252):1081-5 PMID: 8599083
  67. RecQ family members combine strand pairing and unwinding activities to catalyze strand exchange.
    J Biol Chem. 2005 Jun 17;280(24):23397-407 PMID: 15845538
  68. Modularity and specialization in superfamily 1 and 2 helicases.
    J Bacteriol. 2002 Apr;184(7):1819-26 PMID: 11889086
  69. Biochemical and kinetic characterization of the DNA helicase and exonuclease activities of werner syndrome protein.
    J Biol Chem. 2004 Aug 13;279(33):34603-13 PMID: 15187093
  70. Conferring substrate specificity to DNA helicases: role of the RecQ HRDC domain.
    Structure. 2005 Aug;13(8):1173-82 PMID: 16084389
  71. The premature ageing syndrome protein, WRN, is a 3'-->5' exonuclease.
    Nat Genet. 1998 Oct;20(2):114-6 PMID: 9771700
  72. A minimal exonuclease domain of WRN forms a hexamer on DNA and possesses both 3'- 5' exonuclease and 5'-protruding strand endonuclease activities.
    Biochemistry. 2002 Mar 5;41(9):2901-12 PMID: 11863428
  73. Structural and functional characterizations reveal the importance of a zinc binding domain in Bloom's syndrome helicase.
    Nucleic Acids Res. 2005 Jun 01;33(10):3109-24 PMID: 15930159
  74. Protein-nucleic acid interactions and the expanding role of mass spectrometry.
    J Biol Chem. 2004 Jun 11;279(24):24907-10 PMID: 15056667
  75. Homologous recombination and maintenance of genome integrity: cancer and aging through the prism of human RecQ helicases.
    Mech Ageing Dev. 2008 Jul-Aug;129(7-8):425-40 PMID: 18430459
  76. The Werner syndrome protein binds replication fork and holliday junction DNAs as an oligomer.
    J Biol Chem. 2008 Sep 5;283(36):24478-83 PMID: 18596042
  77. Structural basis for DNA duplex separation by a superfamily-2 helicase.
    Nat Struct Mol Biol. 2007 Jul;14(7):647-52 PMID: 17558417
  78. Escherichia coli RecQ is a rapid, efficient, and monomeric helicase.
    J Biol Chem. 2006 May 5;281(18):12655-63 PMID: 16507576
  79. The RecQ gene family in plants.
    J Plant Physiol. 2006 Feb;163(3):287-96 PMID: 16371241
  80. Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2.
    Hum Mol Genet. 2004 Sep 1;13(17):1919-32 PMID: 15229185
  81. Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification.
    Hum Mol Genet. 2005 May 15;14(10):1351-65 PMID: 15829507
  82. The Escherichia coli RecQ helicase functions as a monomer.
    J Biol Chem. 2003 Sep 12;278(37):34925-33 PMID: 12805371
  83. A new DNA polymerase species from Drosophila melanogaster: a probable mus308 gene product.
    Mutat Res. 1999 Apr 9;433(3):183-92 PMID: 10343651
  84. Purification of overexpressed hexahistidine-tagged BLM N431 as oligomeric complexes.
    Protein Expr Purif. 1999 Nov;17(2):239-48 PMID: 10545272
  85. Major domain swiveling revealed by the crystal structures of complexes of E. coli Rep helicase bound to single-stranded DNA and ADP.
    Cell. 1997 Aug 22;90(4):635-47 PMID: 9288744
  86. Werner syndrome protein phosphorylation by abl tyrosine kinase regulates its activity and distribution.
    Mol Cell Biol. 2003 Sep;23(18):6385-95 PMID: 12944467
  87. The Bloom's syndrome helicase suppresses crossing over during homologous recombination.
    Nature. 2003 Dec 18;426(6968):870-4 PMID: 14685245
  88. The Saccharomyces cerevisiae Sgs1 helicase efficiently unwinds G-G paired DNAs.
    Nucleic Acids Res. 1999 May 1;27(9):1978-84 PMID: 10198430
  89. DNA helicases: enzymes with essential roles in all aspects of DNA metabolism.
    Bioessays. 1994 Jan;16(1):13-22 PMID: 8141804
  90. Elevation of sister chromatid exchange in Saccharomyces cerevisiae sgs1 disruptants and the relevance of the disruptants as a system to evaluate mutations in Bloom's syndrome gene.
    Mutat Res. 2000 Apr 28;459(3):203-9 PMID: 10812332
  91. A tetramer-octamer equilibrium in Mycobacterium leprae and Escherichia coli RuvA by analytical ultracentrifugation.
    J Mol Biol. 2003 Oct 31;333(4):677-82 PMID: 14568529
  92. Point mutations causing Bloom's syndrome abolish ATPase and DNA helicase activities of the BLM protein.
    Oncogene. 1998 Nov 19;17(20):2565-71 PMID: 9840919
  93. The phage T4-coded DNA replication helicase (gp41) forms a hexamer upon activation by nucleoside triphosphate.
    J Biol Chem. 1995 Mar 31;270(13):7462-73 PMID: 7706292
  94. The HRDC domain of BLM is required for the dissolution of double Holliday junctions.
    EMBO J. 2005 Jul 20;24(14):2679-87 PMID: 15990871
  95. The Bloom's and Werner's syndrome proteins are DNA structure-specific helicases.
    Nucleic Acids Res. 2001 Jul 1;29(13):2843-9 PMID: 11433031
  96. BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase-double Holliday junction dissolvasome.
    Genes Dev. 2008 Oct 15;22(20):2856-68 PMID: 18923083
  97. A putative nucleic acid-binding domain in Bloom's and Werner's syndrome helicases.
    Trends Biochem Sci. 1997 Nov;22(11):417-8 PMID: 9397680
  98. The Bloom's syndrome gene product interacts with topoisomerase III.
    J Biol Chem. 2000 Mar 31;275(13):9636-44 PMID: 10734115
  99. Positional cloning of the Werner's syndrome gene.
    Science. 1996 Apr 12;272(5259):258-62 PMID: 8602509
  100. Winged helix proteins.
    Curr Opin Struct Biol. 2000 Feb;10(1):110-6 PMID: 10679470
  101. Structure and mechanism of helicases and nucleic acid translocases.
    Annu Rev Biochem. 2007;76:23-50 PMID: 17506634
  102. BLAP75/RMI1 promotes the BLM-dependent dissolution of homologous recombination intermediates.
    Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4068-73 PMID: 16537486
  103. RecQ helicases: suppressors of tumorigenesis and premature aging.
    Biochem J. 2003 Sep 15;374(Pt 3):577-606 PMID: 12803543
  104. Intrinsic ssDNA annealing activity in the C-terminal region of WRN.
    Biochemistry. 2008 Sep 30;47(39):10247-54 PMID: 18771289
  105. Different quaternary structures of human RECQ1 are associated with its dual enzymatic activity.
    PLoS Biol. 2007 Feb;5(2):e20 PMID: 17227144
  106. Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome.
    Cell. 2005 Jun 17;121(6):887-98 PMID: 15960976
  107. Rothmund-thomson syndrome responsible gene, RECQL4: genomic structure and products.
    Genomics. 1999 Nov 1;61(3):268-76 PMID: 10552928
  108. DNA binding and nucleotide flipping by the human DNA repair protein AGT.
    Nat Struct Mol Biol. 2004 Aug;11(8):714-20 PMID: 15221026
  109. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene.
    J Med Genet. 2006 Feb;43(2):148-52 PMID: 15964893
  110. Role for BLM in replication-fork restart and suppression of origin firing after replicative stress.
    Nat Struct Mol Biol. 2007 Jul;14(7):677-9 PMID: 17603497
  111. UvrD helicase unwinds DNA one base pair at a time by a two-part power stroke.
    Cell. 2006 Dec 29;127(7):1349-60 PMID: 17190599
  112. Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability.
    Biochem J. 2006 Sep 15;398(3):319-37 PMID: 16925525
  113. Human werner syndrome DNA helicase unwinds tetrahelical structures of the fragile X syndrome repeat sequence d(CGG)n.
    J Biol Chem. 1999 Apr 30;274(18):12797-802 PMID: 10212265
  114. The Bloom's syndrome gene product promotes branch migration of holliday junctions.
    Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6504-8 PMID: 10823897
Article Info
Journal
HFSP journal
Abbr.
HFSP J
ISSN
1955-2068
Published
2009-06-00
Epub
2009-00-18
Pages
153-64
Language
English
Region
France
NLM ID
101299182
PMCID
PMC2714954
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]