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PMID: 19911388 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Unwinding protein complexes in ALTernative telomere maintenance.

Journal of cellular biochemistry ·Vol. 109 ·No. 1 ·2010-01-01 ·Pages 7-15

Bhattacharyya S, Sandy A, Groden J

Abstract

Telomeres are composed of specialized chromatin that includes DNA repair/recombination proteins, telomere DNA-binding proteins and a number of three dimensional nucleic acid structures including G-quartets and D-loops. A number of studies suggest that the BLM and WRN recQ-like helicases play important roles in recombination-mediated mechanisms of telomere elongation or Alternative Lengthening of Telomeres (ALT), processes that maintain/elongate telomeres in the absence of telomerase. BLM and WRN localize within ALT-associated nuclear bodies in telomerase-negative immortalized cell lines and interact with the telomere-specific proteins POT1, TRF1 and TRF2. Helicase activity is modulated by these interactions. BLM functions in DNA double-strand break repair processes such as non-homologous end joining, homologous recombination-mediated repair, resolution of stalled replication forks and synthesis-dependent strand annealing, although its precise functions at the telomeres are speculative. WRN also functions in DNA replication, recombination and repair, and in addition to its helicase domain, includes an exonuclease domain not found in other recQ-like helicases. The biochemical properties of BLM and WRN are, therefore, important in biological processes other than DNA replication, recombination and repair. In this review, we discuss some previous and recent findings of human rec-Q-like helicases and their role in telomere elongation during ALT processes.

MeSH Terms
Animals Humans RecQ Helicases/physiology Telomere/chemistry,physiology Telomere-Binding Proteins/physiology
Chemicals
Telomere-Binding Proteins RecQ Helicases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Bhattacharyya Saumitri
Department of Molecular Virology, Immunology & Medical Genetics, The Ohio State University College of Medicine, 460 W 12th Avenue, 986 Biomedical Research Tower, Columbus, Ohio 43210-2207, USA.
Sandy April
Groden Joanna
References (87)
87 references, click to expand
  1. An alternative pathway for yeast telomere maintenance rescues est1- senescence.
    Cell. 1993 Apr 23;73(2):347-60 PMID: 8477448
  2. Functional role of BLAP75 in BLM-topoisomerase IIIalpha-dependent holliday junction processing.
    J Biol Chem. 2008 Jun 6;283(23):15701-8 PMID: 18390547
  3. Cell cycle regulation of the endogenous wild type Bloom's syndrome DNA helicase.
    Oncogene. 2000 May 25;19(23):2731-8 PMID: 10851073
  4. Human telomeres are attached to the nuclear matrix.
    EMBO J. 1992 Feb;11(2):717-24 PMID: 1537344
  5. Telomerase-associated protein TEP1 is not essential for telomerase activity or telomere length maintenance in vivo.
    Mol Cell Biol. 2000 Nov;20(21):8178-84 PMID: 11027287
  6. Homologous recombination in human telomerase-positive and ALT cells occurs with the same frequency.
    EMBO Rep. 2003 Dec;4(12):1138-43 PMID: 14618159
  7. Telomere and ribosomal DNA repeats are chromosomal targets of the bloom syndrome DNA helicase.
    BMC Cell Biol. 2003 Oct 27;4:15 PMID: 14577841
  8. 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
  9. The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis.
    Hum Mol Genet. 2002 Dec 1;11(25):3135-44 PMID: 12444098
  10. Telomere lengths of translocation-associated and nontranslocation-associated sarcomas differ dramatically.
    Am J Pathol. 2004 May;164(5):1523-9 PMID: 15111298
  11. 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
  12. The RecQ helicase-topoisomerase III-Rmi1 complex: a DNA structure-specific 'dissolvasome'?
    Trends Biochem Sci. 2007 Dec;32(12):538-46 PMID: 17980605
  13. Telomere-bound TRF1 and TRF2 stall the replication fork at telomeric repeats.
    Nucleic Acids Res. 2004 Mar 08;32(5):1627-37 PMID: 15007108
  14. Telomere-telomere recombination is an efficient bypass pathway for telomere maintenance in Saccharomyces cerevisiae.
    Mol Cell Biol. 1999 Dec;19(12):8083-93 PMID: 10567534
  15. Topoisomerase IIIalpha is required for normal proliferation and telomere stability in alternative lengthening of telomeres.
    EMBO J. 2008 May 21;27(10):1513-24 PMID: 18418389
  16. The Bloom's syndrome helicase unwinds G4 DNA.
    J Biol Chem. 1998 Oct 16;273(42):27587-92 PMID: 9765292
  17. Cloning of two new human helicase genes of the RecQ family: biological significance of multiple species in higher eukaryotes.
    Genomics. 1998 Dec 15;54(3):443-52 PMID: 9878247
  18. Accelerated loss of telomeric repeats may not explain accelerated replicative decline of Werner syndrome cells.
    Hum Genet. 1996 Jun;97(6):750-4 PMID: 8641691
  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. The Bloom's syndrome protein (BLM) interacts with MLH1 but is not required for DNA mismatch repair.
    J Biol Chem. 2001 Aug 10;276(32):30031-5 PMID: 11325959
  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. Impaired S-phase transit of Werner syndrome cells expressed in lymphoblastoid cell lines.
    Exp Cell Res. 1992 Oct;202(2):267-73 PMID: 1327851
  23. POT1 stimulates RecQ helicases WRN and BLM to unwind telomeric DNA substrates.
    J Biol Chem. 2005 Sep 16;280(37):32069-80 PMID: 16030011
  24. A role for PML and the nuclear body in genomic stability.
    Oncogene. 1999 Dec 23;18(56):7941-7 PMID: 10637504
  25. Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells.
    Nucleic Acids Res. 2004 Jul 16;32(12):3743-51 PMID: 15258249
  26. BLM and the FANC proteins collaborate in a common pathway in response to stalled replication forks.
    EMBO J. 2004 Aug 4;23(15):3154-63 PMID: 15257300
  27. Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway.
    Genes Dev. 2005 Nov 1;19(21):2560-70 PMID: 16264192
  28. Telomere maintenance by recombination in human cells.
    Nat Genet. 2000 Dec;26(4):447-50 PMID: 11101843
  29. Telomere dynamics and telomerase activity in in vitro immortalised human cells.
    Eur J Cancer. 1997 Apr;33(5):767-73 PMID: 9282115
  30. Unusual DNA sequences associated with the ends of yeast chromosomes.
    Nature. 1984 Jul 12-18;310(5973):157-60 PMID: 6377091
  31. A survey of telomerase activity in human cancer.
    Eur J Cancer. 1997 Apr;33(5):787-91 PMID: 9282118
  32. NBS1 and TRF1 colocalize at promyelocytic leukemia bodies during late S/G2 phases in immortalized telomerase-negative cells. Implication of NBS1 in alternative lengthening of telomeres.
    J Biol Chem. 2000 Sep 29;275(39):30618-22 PMID: 10913111
  33. Abnormal telomere dynamics of B-lymphoblastoid cell strains from Werner's syndrome patients transformed by Epstein-Barr virus.
    Oncogene. 1997 Oct 16;15(16):1911-20 PMID: 9365237
  34. Alternative lengthening of telomeres, telomerase, and cancer.
    Cancer Lett. 2003 May 15;194(2):155-62 PMID: 12757973
  35. Human telomeres contain at least three types of G-rich repeat distributed non-randomly.
    Nucleic Acids Res. 1989 Jun 26;17(12):4611-27 PMID: 2664709
  36. The Saccharomyces cerevisiae WRN homolog Sgs1p participates in telomere maintenance in cells lacking telomerase.
    EMBO J. 2001 Feb 15;20(4):905-13 PMID: 11179234
  37. Mutator phenotype of Werner syndrome is characterized by extensive deletions.
    Proc Natl Acad Sci U S A. 1989 Aug;86(15):5893-7 PMID: 2762303
  38. The frequency of homologous recombination in human ALT cells.
    Cell Cycle. 2004 May;3(5):547-9 PMID: 15034305
  39. Telomere elongation in immortal human cells without detectable telomerase activity.
    EMBO J. 1995 Sep 1;14(17):4240-8 PMID: 7556065
  40. The C-terminal domain of the Bloom syndrome DNA helicase is essential for genomic stability.
    BMC Cell Biol. 2001;2:11 PMID: 11472631
  41. Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body.
    Cancer Res. 1999 Sep 1;59(17):4175-9 PMID: 10485449
  42. 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
  43. Nuclear structure in normal and Bloom syndrome cells.
    Proc Natl Acad Sci U S A. 2000 May 9;97(10):5214-9 PMID: 10779560
  44. Excess of rare cancers in Werner syndrome (adult progeria).
    Cancer Epidemiol Biomarkers Prev. 1996 Apr;5(4):239-46 PMID: 8722214
  45. DNA topoisomerases: structure, function, and mechanism.
    Annu Rev Biochem. 2001;70:369-413 PMID: 11395412
  46. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity.
    Science. 2004 Dec 10;306(5703):1951-3 PMID: 15591207
  47. Extra-chromosomal telomere repeat DNA in telomerase-negative immortalized cell lines.
    Biochem Biophys Res Commun. 1998 Jun 29;247(3):765-72 PMID: 9647768
  48. Telomerase-associated protein 1, HSP90, and topoisomerase IIalpha associate directly with the BLM helicase in immortalized cells using ALT and modulate its helicase activity using telomeric DNA substrates.
    J Biol Chem. 2009 May 29;284(22):14966-77 PMID: 19329795
  49. ALT-associated PML bodies are present in viable cells and are enriched in cells in the G(2)/M phase of the cell cycle.
    J Cell Sci. 2000 Dec;113 Pt 24:4577-85 PMID: 11082050
  50. WRN interacts physically and functionally with the recombination mediator protein RAD52.
    J Biol Chem. 2003 Sep 19;278(38):36476-86 PMID: 12750383
  51. Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM.
    J Biol Chem. 2002 Aug 23;277(34):30515-23 PMID: 12034743
  52. Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks.
    J Cell Biol. 2003 Sep 29;162(7):1197-209 PMID: 14517203
  53. Detection of quadruplex DNA structures in human telomeres by a fluorescent carbazole derivative.
    Anal Chem. 2004 Aug 1;76(15):4490-4 PMID: 15283592
  54. A novel telomere structure in a human alternative lengthening of telomeres cell line.
    Cancer Res. 2005 Apr 1;65(7):2730-7 PMID: 15805272
  55. TRF1 promotes parallel pairing of telomeric tracts in vitro.
    J Mol Biol. 1998 Apr 24;278(1):79-88 PMID: 9571035
  56. Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice.
    J Cell Biol. 1999 Feb 22;144(4):589-601 PMID: 10037783
  57. DNA topoisomerases.
    Annu Rev Biochem. 1996;65:635-92 PMID: 8811192
  58. Bloom's syndrome protein is required for correct relocalization of RAD50/MRE11/NBS1 complex after replication fork arrest.
    J Cell Biol. 2002 Apr 1;157(1):19-30 PMID: 11916980
  59. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome.
    Mol Cell Biol. 2003 May;23(10):3417-26 PMID: 12724401
  60. 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
  61. FEN1 contributes to telomere stability in ALT-positive tumor cells.
    Oncogene. 2009 Feb 26;28(8):1162-7 PMID: 19137021
  62. Alternative lengthening of telomeres is characterized by high rates of telomeric exchange.
    Cancer Res. 2004 Apr 1;64(7):2324-7 PMID: 15059879
  63. DNA sequences of telomeres maintained in yeast.
    Nature. 1984 Jul 12-18;310(5973):154-7 PMID: 6330571
  64. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures.
    Genes Dev. 2000 Apr 15;14(8):927-39 PMID: 10783165
  65. The gene responsible for Werner syndrome may be a cell division "counting" gene.
    Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):12030-4 PMID: 8265666
  66. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines.
    Nat Med. 1997 Nov;3(11):1271-4 PMID: 9359704
  67. Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts.
    Nat Genet. 2000 Jan;24(1):16-7 PMID: 10615119
  68. 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
  69. Telomere maintenance in telomerase-deficient mouse embryonic stem cells: characterization of an amplified telomeric DNA.
    Mol Cell Biol. 2000 Jun;20(11):4115-27 PMID: 10805753
  70. Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1.
    Nucleic Acids Res. 2001 Nov 1;29(21):4378-86 PMID: 11691925
  71. The Bloom's syndrome gene product interacts with topoisomerase III.
    J Biol Chem. 2000 Mar 31;275(13):9636-44 PMID: 10734115
  72. Mammalian telomeres end in a large duplex loop.
    Cell. 1999 May 14;97(4):503-14 PMID: 10338214
  73. Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins.
    J Biol Chem. 2002 Jun 14;277(24):22035-44 PMID: 11919194
  74. 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
  75. BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination.
    EMBO J. 2003 Mar 3;22(5):1210-22 PMID: 12606585
  76. Recombinational telomere elongation promoted by DNA circles.
    Mol Cell Biol. 2002 Jul;22(13):4512-21 PMID: 12052861
  77. Functional requirement of p23 and Hsp90 in telomerase complexes.
    Genes Dev. 1999 Apr 1;13(7):817-26 PMID: 10197982
  78. Inhibition of the Bloom's and Werner's syndrome helicases by G-quadruplex interacting ligands.
    Biochemistry. 2001 Dec 18;40(50):15194-202 PMID: 11735402
  79. G4 DNA unwinding by BLM and Sgs1p: substrate specificity and substrate-specific inhibition.
    Nucleic Acids Res. 2002 Sep 15;30(18):3954-61 PMID: 12235379
  80. Binding and melting of D-loops by the Bloom syndrome helicase.
    Biochemistry. 2000 Nov 28;39(47):14617-25 PMID: 11087418
  81. Structure and variability of human chromosome ends.
    Mol Cell Biol. 1990 Feb;10(2):518-27 PMID: 2300052
  82. The human decatenation checkpoint.
    Proc Natl Acad Sci U S A. 2001 Oct 9;98(21):12044-9 PMID: 11593014
  83. Telomerase activity and telomere lengths in various cell lines: changes of telomerase activity can be another method for chemosensitivity evaluation.
    Int J Oncol. 1998 Sep;13(3):489-95 PMID: 9683783
  84. Vaults and telomerase share a common subunit, TEP1.
    J Biol Chem. 1999 Nov 12;274(46):32712-7 PMID: 10551828
  85. A role for monoubiquitinated FANCD2 at telomeres in ALT cells.
    Nucleic Acids Res. 2009 Apr;37(6):1740-54 PMID: 19129235
  86. Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases.
    J Biol Chem. 2002 Oct 25;277(43):41110-9 PMID: 12181313
  87. TRF1 is a dimer and bends telomeric DNA.
    EMBO J. 1997 Apr 1;16(7):1785-94 PMID: 9130722
Article Info
Journal
Journal of cellular biochemistry
Abbr.
J Cell Biochem
ISSN
1097-4644
Published
2010-01-01
Pages
7-15
Language
English
Region
United States
NLM ID
8205768
PMCID
PMC2892175
Subset
IM
Grants
NCI NIH HHS · R01 CA117898 · United States
NCI NIH HHS · R01 CA117898-02 · United States
NCI NIH HHS · CA-117898 · United States
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