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PMID: 15990871 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The HRDC domain of BLM is required for the dissolution of double Holliday junctions.

The EMBO journal ·Vol. 24 ·No. 14 ·2005-07-20 ·Pages 2679-87

Wu L, Chan KL, Ralf C, Bernstein DA, Garcia PL, Bohr VA, Vindigni A, Janscak P, Keck JL, Hickson ID

Abstract

Bloom's syndrome is a hereditary cancer-predisposition disorder resulting from mutations in the BLM gene. In humans, BLM encodes one of five members of the RecQ helicase family. One function of BLM is to act in concert with topoisomerase IIIalpha (TOPO IIIalpha) to resolve recombination intermediates containing double Holliday junctions by a process called double Holliday junction dissolution, herein termed dissolution. Here, we show that dissolution is highly specific for BLM among human RecQ helicases and critically depends upon a functional HRDC domain in BLM. We show that the HRDC domain confers DNA structure specificity, and is required for the efficient binding to and unwinding of double Holliday junctions, but not for the unwinding of a simple partial duplex substrate. Furthermore, we show that lysine-1270 of BLM, which resides in the HRDC domain and is predicted to play a role in mediating interactions with DNA, is required for efficient dissolution.

MeSH Terms
Adenosine Triphosphatases/genetics,metabolism Amino Acid Sequence Bloom Syndrome/genetics,metabolism DNA Helicases/genetics,metabolism DNA, Cruciform/metabolism Humans Lysine/metabolism Molecular Sequence Data Protein Structure, Tertiary RecQ Helicases Sequence Analysis, Protein
Chemicals
DNA, Cruciform Adenosine Triphosphatases Bloom syndrome protein DNA Helicases RecQ Helicases Lysine
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Wu Leonard
Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
Chan Kok Lung
Ralf Christine
Bernstein Douglas A
Garcia Patrick L
Bohr Vilhelm A
Vindigni Alessandro
Janscak Pavel
Keck James L
Hickson Ian D
References (56)
56 references, click to expand
  1. RecQ helicase and topoisomerase III comprise a novel DNA strand passage function: a conserved mechanism for control of DNA recombination.
    Mol Cell. 1999 May;3(5):611-20 PMID: 10360177
  2. Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts.
    Nat Genet. 2000 Jan;24(1):16-7 PMID: 10615119
  3. 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
  4. 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
  5. The Bloom's syndrome gene product interacts with topoisomerase III.
    J Biol Chem. 2000 Mar 31;275(13):9636-44 PMID: 10734115
  6. 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
  7. Interaction between yeast sgs1 helicase and DNA topoisomerase III.
    J Biol Chem. 2000 Sep 1;275(35):26898-905 PMID: 10862619
  8. Cancer predisposition caused by elevated mitotic recombination in Bloom mice.
    Nat Genet. 2000 Dec;26(4):424-9 PMID: 11101838
  9. Mapping the DNA topoisomerase III binding domain of the Sgs1 DNA helicase.
    J Biol Chem. 2001 Mar 23;276(12):8848-55 PMID: 11124263
  10. Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability.
    Hum Mol Genet. 2001 Jun 1;10(12):1287-98 PMID: 11406610
  11. 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
  12. RecQ helicases and topoisomerases: components of a conserved complex for the regulation of genetic recombination.
    Cell Mol Life Sci. 2001 Jun;58(7):894-901 PMID: 11497238
  13. Association of yeast DNA topoisomerase III and Sgs1 DNA helicase: studies of fusion proteins.
    Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11108-13 PMID: 11553789
  14. Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity.
    EMBO J. 2001 Oct 15;20(20):5791-801 PMID: 11598021
  15. Human Mus81-associated endonuclease cleaves Holliday junctions in vitro.
    Mol Cell. 2001 Nov;8(5):1117-27 PMID: 11741546
  16. Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins.
    J Biol Chem. 2002 Jun 14;277(24):22035-44 PMID: 11919194
  17. The C-terminal domain of the Bloom syndrome DNA helicase is essential for genomic stability.
    BMC Cell Biol. 2001;2:11 PMID: 11472631
  18. Mutations in homologous recombination genes rescue top3 slow growth in Saccharomyces cerevisiae.
    Genetics. 2002 Oct;162(2):647-62 PMID: 12399378
  19. RecQ helicases and cellular responses to DNA damage.
    Mutat Res. 2002 Nov 30;509(1-2):35-47 PMID: 12427530
  20. The Bloom's syndrome helicase stimulates the activity of human topoisomerase IIIalpha.
    Nucleic Acids Res. 2002 Nov 15;30(22):4823-9 PMID: 12433984
  21. Defending genome integrity during S-phase: putative roles for RecQ helicases and topoisomerase III.
    DNA Repair (Amst). 2002 Mar 28;1(3):175-207 PMID: 12509252
  22. Inactivation of homologous recombination suppresses defects in topoisomerase III-deficient mutants.
    DNA Repair (Amst). 2002 Jun 21;1(6):463-82 PMID: 12509234
  23. RecQ helicases: caretakers of the genome.
    Nat Rev Cancer. 2003 Mar;3(3):169-78 PMID: 12612652
  24. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.
    Mol Cell Biol. 2003 May;23(10):3417-26 PMID: 12724401
  25. Functional relation among RecQ family helicases RecQL1, RecQL5, and BLM in cell growth and sister chromatid exchange formation.
    Mol Cell Biol. 2003 May;23(10):3527-35 PMID: 12724411
  26. 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
  27. Molecular views of recombination proteins and their control.
    Nat Rev Mol Cell Biol. 2003 Jun;4(6):435-45 PMID: 12778123
  28. RecQ helicases: suppressors of tumorigenesis and premature aging.
    Biochem J. 2003 Sep 15;374(Pt 3):577-606 PMID: 12803543
  29. Purification and characterization of human DNA topoisomerase IIIalpha.
    Nucleic Acids Res. 1999 Jun 15;27(12):2443-50 PMID: 10352172
  30. Functional and physical interaction between WRN helicase and human replication protein A.
    J Biol Chem. 1999 Jun 25;274(26):18341-50 PMID: 10373438
  31. Transfection of BLM into cultured bloom syndrome cells reduces the sister-chromatid exchange rate toward normal.
    Am J Hum Genet. 1999 Nov;65(5):1368-74 PMID: 10521302
  32. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity.
    Science. 2004 Dec 10;306(5703):1951-3 PMID: 15591207
  33. High-resolution structure of the E.coli RecQ helicase catalytic core.
    EMBO J. 2003 Oct 1;22(19):4910-21 PMID: 14517231
  34. Generating crossovers by resolution of nicked Holliday junctions: a role for Mus81-Eme1 in meiosis.
    Mol Cell. 2003 Sep;12(3):761-74 PMID: 14527420
  35. Srs2 and Sgs1-Top3 suppress crossovers during double-strand break repair in yeast.
    Cell. 2003 Nov 14;115(4):401-11 PMID: 14622595
  36. The Bloom's syndrome helicase suppresses crossing over during homologous recombination.
    Nature. 2003 Dec 18;426(6968):870-4 PMID: 14685245
  37. RAD51C is required for Holliday junction processing in mammalian cells.
    Science. 2004 Jan 9;303(5655):243-6 PMID: 14716019
  38. Phosphorylation of the Bloom's syndrome helicase and its role in recovery from S-phase arrest.
    Mol Cell Biol. 2004 Feb;24(3):1279-91 PMID: 14729972
  39. Analysis of the unwinding activity of the dimeric RECQ1 helicase in the presence of human replication protein A.
    Nucleic Acids Res. 2004;32(7):2158-70 PMID: 15096578
  40. The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2.
    Mol Cell. 2004 Jun 18;14(6):763-74 PMID: 15200954
  41. 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
  42. Essential role of limiting telomeres in the pathogenesis of Werner syndrome.
    Nat Genet. 2004 Aug;36(8):877-82 PMID: 15235603
  43. Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes.
    Mol Cell Biol. 2004 Oct;24(19):8437-46 PMID: 15367665
  44. A manyfold increase in sister chromatid exchanges in Bloom's syndrome lymphocytes.
    Proc Natl Acad Sci U S A. 1974 Nov;71(11):4508-12 PMID: 4140506
  45. A hyper-recombination mutation in S. cerevisiae identifies a novel eukaryotic topoisomerase.
    Cell. 1989 Jul 28;58(2):409-19 PMID: 2546682
  46. DNA double-strand break repair: genetic determinants of flanking crossing-over.
    Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1173-7 PMID: 8302849
  47. Holliday junction crossover topology.
    J Mol Biol. 1994 Feb 11;236(1):91-105 PMID: 8107128
  48. The yeast type I topoisomerase Top3 interacts with Sgs1, a DNA helicase homolog: a potential eukaryotic reverse gyrase.
    Mol Cell Biol. 1994 Dec;14(12):8391-8 PMID: 7969174
  49. The Bloom's syndrome gene product is homologous to RecQ helicases.
    Cell. 1995 Nov 17;83(4):655-66 PMID: 7585968
  50. Positional cloning of the Werner's syndrome gene.
    Science. 1996 Apr 12;272(5259):258-62 PMID: 8602509
  51. SGS1, a homologue of the Bloom's and Werner's syndrome genes, is required for maintenance of genome stability in Saccharomyces cerevisiae.
    Genetics. 1996 Nov;144(3):935-45 PMID: 8913739
  52. The Bloom's syndrome gene product is a 3'-5' DNA helicase.
    J Biol Chem. 1997 Dec 5;272(49):30611-4 PMID: 9388193
  53. 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
  54. The premature ageing syndrome protein, WRN, is a 3'-->5' exonuclease.
    Nat Genet. 1998 Oct;20(2):114-6 PMID: 9771700
  55. Werner syndrome protein. II. Characterization of the integral 3' --> 5' DNA exonuclease.
    J Biol Chem. 1998 Dec 18;273(51):34145-50 PMID: 9852074
  56. Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome.
    Nat Genet. 1999 May;22(1):82-4 PMID: 10319867
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7600740
Published
2005-07-20
Epub
2005-00-30
Pages
2679-87
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1176466
Subset
IM
External Links
PubMed source DOI: 10.1038/sj.emboj.7600740 PMC Full Text View journal details
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