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PMID: 16809776 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural

Control of translocations between highly diverged genes by Sgs1, the Saccharomyces cerevisiae homolog of the Bloom's syndrome protein.

Molecular and cellular biology ·Vol. 26 ·No. 14 ·2006-07-00 ·Pages 5406-20

Schmidt KH, Wu J, Kolodner RD

Abstract

Sgs1 is a RecQ family DNA helicase required for genome stability in Saccharomyces cerevisiae whose human homologs BLM, WRN, and RECQL4 are mutated in Bloom's, Werner, and Rothmund Thomson syndromes, respectively. Sgs1 and mismatch repair (MMR) are inhibitors of recombination between similar but divergent (homeologous) DNA sequences. Here we show that SGS1, but not MMR, is critical for suppressing spontaneous, recurring translocations between diverged genes in cells with mutations in the genes encoding the checkpoint proteins Mec3, Rad24, Rad9, or Rfc5, the chromatin assembly factors Cac1 or Asf1, and the DNA helicase Rrm3. The S-phase checkpoint kinase and telomere maintenance factor Tel1, a homolog of the human ataxia telangiectasia (ATM) protein, prevents these translocations, whereas the checkpoint kinase Mec1, a homolog of the human ATM-related protein, and the Rad53 checkpoint kinase are not required. The translocation structures observed suggest involvement of a dicentric intermediate and break-induced replication with multiple cycles of DNA template switching.

MeSH Terms
Adenosine Triphosphatases/genetics,metabolism Amino Acid Transport Systems, Basic/genetics,metabolism Base Pair Mismatch Base Sequence Bloom Syndrome/genetics,metabolism DNA Helicases/genetics,metabolism DNA, Fungal/genetics DNA-Binding Proteins/genetics,metabolism Genes, Fungal Humans Molecular Sequence Data Mutation RecQ Helicases Saccharomyces cerevisiae/genetics,metabolism Saccharomyces cerevisiae Proteins/genetics,metabolism Species Specificity Suppression, Genetic Translocation, Genetic
Chemicals
Amino Acid Transport Systems, Basic CAN1 protein, S cerevisiae DNA, Fungal DNA-Binding Proteins LYP1 protein, S cerevisiae Saccharomyces cerevisiae Proteins Adenosine Triphosphatases Bloom syndrome protein SGS1 protein, S cerevisiae DNA Helicases RecQ Helicases
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Schmidt Kristina H
Department of Biology, University of South Florida, 4202 E. Fowler Avenue, SCA110, Tampa, FL 33620, USA. [email protected]
Wu Joann
Kolodner Richard D
References (106)
106 references, click to expand
  1. Chromosomal localization of the gene encoding the human DNA helicase RECQL and its mouse homologue.
    Genomics. 1995 Apr 10;26(3):595-8 PMID: 7607686
  2. Rothmund-Thomson syndrome in siblings: evidence for acquired in vivo mosaicism.
    Clin Genet. 1996 Mar;49(3):124-9 PMID: 8737976
  3. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome.
    J Natl Cancer Inst. 2003 May 7;95(9):669-74 PMID: 12734318
  4. Saccharomyces cerevisiae chromatin-assembly factors that act during DNA replication function in the maintenance of genome stability.
    Proc Natl Acad Sci U S A. 2003 May 27;100(11):6640-5 PMID: 12750463
  5. Replication fork pausing and recombination or "gimme a break".
    Genes Dev. 2000 Jan 1;14(1):1-10 PMID: 10640269
  6. Clonal lines of aneuploid cells in Rothmund-Thomson syndrome.
    Am J Med Genet. 1990 Nov;37(3):336-9 PMID: 2260560
  7. Multiple pathways cooperate in the suppression of genome instability in Saccharomyces cerevisiae.
    Nature. 2001 Jun 28;411(6841):1073-6 PMID: 11429610
  8. Sgs1: a eukaryotic homolog of E. coli RecQ that interacts with topoisomerase II in vivo and is required for faithful chromosome segregation.
    Cell. 1995 Apr 21;81(2):253-60 PMID: 7736577
  9. 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
  10. DNA polymerase stabilization at stalled replication forks requires Mec1 and the RecQ helicase Sgs1.
    EMBO J. 2003 Aug 15;22(16):4325-36 PMID: 12912929
  11. p53's double life: transactivation-independent repression of homologous recombination.
    Trends Genet. 2004 Jun;20(6):235-43 PMID: 15145576
  12. Mismatch correction acts as a barrier to homeologous recombination in Saccharomyces cerevisiae.
    Genetics. 1995 Mar;139(3):1175-88 PMID: 7768431
  13. Systematic genetic analysis with ordered arrays of yeast deletion mutants.
    Science. 2001 Dec 14;294(5550):2364-8 PMID: 11743205
  14. Spontaneous chromosomal aberrations in Fanconi anaemia, ataxia telangiectasia fibroblast and Bloom's syndrome lymphoblastoid cell lines as detected by conventional cytogenetic analysis and fluorescence in situ hybridisation (FISH) technique.
    Mutat Res. 1995 Feb;334(1):59-69 PMID: 7799980
  15. Homologous recombination is responsible for cell death in the absence of the Sgs1 and Srs2 helicases.
    Nat Genet. 2000 Jun;25(2):192-4 PMID: 10835635
  16. Colorectal cancer without high microsatellite instability and chromosomal instability--an alternative genetic pathway to human colorectal cancer.
    Carcinogenesis. 2004 May;25(5):841-6 PMID: 14729584
  17. Maintenance of genome stability in Saccharomyces cerevisiae.
    Science. 2002 Jul 26;297(5581):552-7 PMID: 12142524
  18. Non-random chromosomal aberrations in a complex leukaemic clone of a Bloom's syndrome patient.
    Hum Genet. 1988 Nov;80(3):311-4 PMID: 3192221
  19. ATM: the protein encoded by the gene mutated in the radiosensitive syndrome ataxia-telangiectasia.
    Int J Radiat Biol. 1999 Oct;75(10):1201-14 PMID: 10549596
  20. Break-induced replication: a review and an example in budding yeast.
    Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8255-62 PMID: 11459961
  21. Genomic instability and colon cancer.
    Cancer Metastasis Rev. 2004 Jan-Jun;23(1-2):11-27 PMID: 15000146
  22. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer.
    Cell. 1993 Dec 17;75(6):1215-25 PMID: 8261515
  23. Instability of lymphocyte chromosomes in a girl with Rothmund-Thomson syndrome.
    J Med Genet. 1994 Jul;31(7):570-2 PMID: 7966195
  24. Mechanistically distinct roles for Sgs1p in checkpoint activation and replication fork maintenance.
    EMBO J. 2005 Jan 26;24(2):405-17 PMID: 15616582
  25. The Bloom's syndrome gene product is homologous to RecQ helicases.
    Cell. 1995 Nov 17;83(4):655-66 PMID: 7585968
  26. Role of mismatch repair in the fidelity of RAD51- and RAD59-dependent recombination in Saccharomyces cerevisiae.
    Genetics. 2003 Dec;165(4):1733-44 PMID: 14704162
  27. 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
  28. Homologous and homeologous intermolecular gene conversion are not differentially affected by mutations in the DNA damage or the mismatch repair genes RAD1, RAD50, RAD51, RAD52, RAD54, PMS1 and MSH2.
    Genetics. 1996 Jun;143(2):755-67 PMID: 8725224
  29. Cloning and characterization of RECQL, a potential human homologue of the Escherichia coli DNA helicase RecQ.
    J Biol Chem. 1994 Nov 25;269(47):29838-45 PMID: 7961977
  30. 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
  31. Myelodysplastic syndrome associated with monosomy 7 in a child with Bloom syndrome.
    Cancer Genet Cytogenet. 2000 Jan 1;116(1):44-6 PMID: 10616531
  32. Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast.
    Nat Genet. 2004 Jun;36(6):612-7 PMID: 15133512
  33. Suppression of spontaneous chromosomal rearrangements by S phase checkpoint functions in Saccharomyces cerevisiae.
    Cell. 2001 Feb 9;104(3):397-408 PMID: 11239397
  34. 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
  35. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients.
    Am J Med Genet. 2001 Jul 22;102(1):11-7 PMID: 11471165
  36. Characterization of sporadic colon cancer by patterns of genomic instability.
    Cancer Res. 2003 Apr 1;63(7):1608-14 PMID: 12670912
  37. Chromosomal aberrations in Bloom syndrome patients with myeloid malignancies.
    Cancer Genet Cytogenet. 2001 Jul 1;128(1):39-42 PMID: 11454428
  38. A biological network in Saccharomyces cerevisiae prevents the deleterious effects of endogenous oxidative DNA damage.
    Mol Cell. 2005 Mar 4;17(5):709-20 PMID: 15749020
  39. Alternate pathways involving Sgs1/Top3, Mus81/ Mms4, and Srs2 prevent formation of toxic recombination intermediates from single-stranded gaps created by DNA replication.
    Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16887-92 PMID: 12475932
  40. Bipartite structure of the SGS1 DNA helicase in Saccharomyces cerevisiae.
    Genetics. 2000 Mar;154(3):1101-14 PMID: 10757756
  41. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer.
    Cell. 1993 Dec 3;75(5):1027-38 PMID: 8252616
  42. Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome.
    Cell. 2005 Jun 17;121(6):887-98 PMID: 15960976
  43. Multiple regulators of Ty1 transposition in Saccharomyces cerevisiae have conserved roles in genome maintenance.
    Genetics. 2001 Dec;159(4):1449-65 PMID: 11779788
  44. Cytogenetic study in a mentally retarded child with Bloom syndrome and acute lymphoblastic leukemia.
    Am J Med Genet. 1984 Jun;18(2):215-21 PMID: 6589956
  45. Positional cloning of the Werner's syndrome gene.
    Science. 1996 Apr 12;272(5259):258-62 PMID: 8602509
  46. Chromosomal instability in fibroblasts and mesenchymal tumors from 2 sibs with Rothmund-Thomson syndrome.
    Int J Cancer. 1998 Aug 12;77(4):504-10 PMID: 9679749
  47. Biochemical characterization of the RECQ4 protein, mutated in Rothmund-Thomson syndrome.
    DNA Repair (Amst). 2006 Feb 3;5(2):172-80 PMID: 16214424
  48. The yeast Xrs2 complex functions in S phase checkpoint regulation.
    Genes Dev. 2001 Sep 1;15(17):2238-49 PMID: 11544181
  49. Bloom's syndrome complicated by myelodysplastic syndrome and multiple neoplasia.
    Intern Med. 1993 May;32(5):399-402 PMID: 8400502
  50. DNA helicase gene interaction network defined using synthetic lethality analyzed by microarray.
    Nat Genet. 2003 Nov;35(3):277-86 PMID: 14566339
  51. Rothmund-Thomson syndrome: review of the world literature.
    J Am Acad Dermatol. 1992 Nov;27(5 Pt 1):750-62 PMID: 1430398
  52. Requirement of yeast SGS1 and SRS2 genes for replication and transcription.
    Science. 1999 Dec 17;286(5448):2339-42 PMID: 10600744
  53. Eukaryotic DNA mismatch repair.
    Curr Opin Genet Dev. 1999 Feb;9(1):89-96 PMID: 10072354
  54. Saccharomyces cerevisiae Rrm3p DNA helicase promotes genome integrity by preventing replication fork stalling: viability of rrm3 cells requires the intra-S-phase checkpoint and fork restart activities.
    Mol Cell Biol. 2004 Apr;24(8):3198-212 PMID: 15060144
  55. Mutant p53 proteins stimulate spontaneous and radiation-induced intrachromosomal homologous recombination independently of the alteration of the transactivation activity and of the G1 checkpoint.
    Oncogene. 1999 Jun 17;18(24):3553-63 PMID: 10380877
  56. Suppression of genome instability by redundant S-phase checkpoint pathways in Saccharomyces cerevisiae.
    Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4500-7 PMID: 11917116
  57. Hypermutability and mismatch repair deficiency in RER+ tumor cells.
    Cell. 1993 Dec 17;75(6):1227-36 PMID: 8261516
  58. RecQ helicases: at the heart of genetic stability.
    FEBS Lett. 2002 Oct 2;529(1):43-8 PMID: 12354611
  59. SGS1, the Saccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homeologous recombination.
    Nat Genet. 2001 Jan;27(1):113-6 PMID: 11138010
  60. Cytogenetics of Werner's syndrome cultured skin fibroblasts: variegated translocation mosaicism.
    Cytogenet Cell Genet. 1981;30(2):92-107 PMID: 7273860
  61. Differential effects of the mismatch repair genes MSH2 and MSH3 on homeologous recombination in Saccharomyces cerevisiae.
    Mol Gen Genet. 1997 Dec;257(1):71-82 PMID: 9439571
  62. Elevated incidence of loss of heterozygosity (LOH) in an sgs1 mutant of Saccharomyces cerevisiae: roles of yeast RecQ helicase in suppression of aneuploidy, interchromosomal rearrangement, and the simultaneous incidence of both events during mitotic growth.
    Mutat Res. 2002 Jul 25;504(1-2):157-72 PMID: 12106656
  63. Genetic instability in colorectal cancers.
    Nature. 1997 Apr 10;386(6625):623-7 PMID: 9121588
  64. Bloom's syndrome. XX. The first 100 cancers.
    Cancer Genet Cytogenet. 1997 Jan;93(1):100-6 PMID: 9062585
  65. Examination of the roles of Sgs1 and Srs2 helicases in the enforcement of recombination fidelity in Saccharomyces cerevisiae.
    Genetics. 2004 Dec;168(4):1855-65 PMID: 15611162
  66. Requirement for three novel protein complexes in the absence of the Sgs1 DNA helicase in Saccharomyces cerevisiae.
    Genetics. 2001 Jan;157(1):103-18 PMID: 11139495
  67. Use of a chromosomal inverted repeat to demonstrate that the RAD51 and RAD52 genes of Saccharomyces cerevisiae have different roles in mitotic recombination.
    Genetics. 1994 Nov;138(3):587-95 PMID: 7851757
  68. 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
  69. Requirement of Rrm3 helicase for repair of spontaneous DNA lesions in cells lacking Srs2 or Sgs1 helicase.
    Mol Cell Biol. 2004 Apr;24(8):3213-26 PMID: 15060145
  70. A DNA damage response pathway controlled by Tel1 and the Mre11 complex.
    Mol Cell. 2001 Jun;7(6):1255-66 PMID: 11430828
  71. Srs2 and Sgs1-Top3 suppress crossovers during double-strand break repair in yeast.
    Cell. 2003 Nov 14;115(4):401-11 PMID: 14622595
  72. Bloom's and Werner's syndrome genes suppress hyperrecombination in yeast sgs1 mutant: implication for genomic instability in human diseases.
    Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8733-8 PMID: 9671747
  73. The yeast Sgs1 helicase is differentially required for genomic and ribosomal DNA replication.
    EMBO J. 2003 Apr 15;22(8):1939-49 PMID: 12682026
  74. The human Rothmund-Thomson syndrome gene product, RECQL4, localizes to distinct nuclear foci that coincide with proteins involved in the maintenance of genome stability.
    J Cell Sci. 2005 Sep 15;118(Pt 18):4261-9 PMID: 16141230
  75. 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
  76. The yeast Sgs1p helicase acts upstream of Rad53p in the DNA replication checkpoint and colocalizes with Rad53p in S-phase-specific foci.
    Genes Dev. 2000 Jan 1;14(1):81-96 PMID: 10640278
  77. DNA substrate dependence of p53-mediated regulation of double-strand break repair.
    Mol Cell Biol. 2002 Sep;22(17):6306-17 PMID: 12167722
  78. Sister chromatids are preferred over homologs as substrates for recombinational repair in Saccharomyces cerevisiae.
    Genetics. 1992 Oct;132(2):387-402 PMID: 1427035
  79. Homologous Recombination and Its Role in Carcinogenesis.
    J Biomed Biotechnol. 2002;2(2):75-85 PMID: 12488587
  80. Mitotic recombination in yeast: elements controlling its incidence.
    Yeast. 2000 Jun 15;16(8):731-54 PMID: 10861900
  81. 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
  82. Chromosomal rearrangements occur in S. cerevisiae rfa1 mutator mutants due to mutagenic lesions processed by double-strand-break repair.
    Mol Cell. 1998 Jul;2(1):9-22 PMID: 9702187
  83. 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
  84. Mitotic crossovers between diverged sequences are regulated by mismatch repair proteins in Saccaromyces cerevisiae.
    Mol Cell Biol. 1996 Mar;16(3):1085-93 PMID: 8622653
  85. Spectral karyotyping suggests additional subsets of colorectal cancers characterized by pattern of chromosome rearrangement.
    Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2538-43 PMID: 11226274
  86. Gross chromosomal rearrangements in Saccharomyces cerevisiae replication and recombination defective mutants.
    Nat Genet. 1999 Sep;23(1):81-5 PMID: 10471504
  87. Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome.
    Nat Genet. 1999 May;22(1):82-4 PMID: 10319867
  88. Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways.
    Science. 1996 Jan 19;271(5247):357-60 PMID: 8553072
  89. Binding specificity determines polarity of DNA unwinding by the Sgs1 protein of S. cerevisiae.
    J Mol Biol. 1999 Jun 4;289(2):235-48 PMID: 10366502
  90. Saccharomyces cerevisiae as a model system to define the chromosomal instability phenotype.
    Mol Cell Biol. 2005 Aug;25(16):7226-38 PMID: 16055731
  91. Elevated spontaneous mutation rate in SV40-transformed Werner syndrome fibroblast cell lines.
    Somat Cell Mol Genet. 1985 Jul;11(4):303-8 PMID: 2992100
  92. A genomewide screen in Saccharomyces cerevisiae for genes that suppress the accumulation of mutations.
    Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11529-34 PMID: 12972632
  93. 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
  94. DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis.
    Oncogene. 1999 Dec 20;18(55):7883-99 PMID: 10630641
  95. 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
  96. Cancer predisposition caused by elevated mitotic recombination in Bloom mice.
    Nat Genet. 2000 Dec;26(4):424-9 PMID: 11101838
  97. Regulation of genome stability by TEL1 and MEC1, yeast homologs of the mammalian ATM and ATR genes.
    Genetics. 2002 Jun;161(2):493-507 PMID: 12072449
  98. Extrachromosomal rDNA circles--a cause of aging in yeast.
    Cell. 1997 Dec 26;91(7):1033-42 PMID: 9428525
  99. Mitotic crossing-over and segregation in man.
    Hum Genet. 1981;59(2):93-100 PMID: 7035337
  100. When replication forks stop.
    Mol Microbiol. 1994 Jul;13(1):17-23 PMID: 7984091
  101. Role of Saccharomyces cerevisiae Msh2 and Msh3 repair proteins in double-strand break-induced recombination.
    Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9214-9 PMID: 9256462
  102. 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
  103. Inactivation of p53 results in high rates of homologous recombination.
    Oncogene. 1997 Apr 17;14(15):1847-57 PMID: 9150391
  104. DNA replication meets genetic exchange: chromosomal damage and its repair by homologous recombination.
    Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8461-8 PMID: 11459990
  105. 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
  106. TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1.
    Cell. 1995 Sep 8;82(5):831-40 PMID: 7545545
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.00161-06
Email
[email protected]
Published
2006-07-00
Pages
5406-20
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1592713
Subset
IM
Grants
NIGMS NIH HHS · GM26017 · United States
NIGMS NIH HHS · R37 GM026017 · United States
NIGMS NIH HHS · R01 GM026017 · United States
NIGMS NIH HHS · GM50006 · United States
NIGMS NIH HHS · R01 GM050006 · United States
External Links
PubMed source DOI: 10.1128/MCB.00161-06 PMC Full Text View journal details
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