Current Genetics

, Volume 52, Issue 5–6, pp 239–245 | Cite as

High rate of starvation-associated mutagenesis in Ung yeast caused by the overproduction of human activation-induced deaminase

  • Angela Lucaccioni
  • Youri I. Pavlov
  • Alessandro Achilli
  • Nora Babudri
Research Article

Abstract

We examined the role of Saccharomyces cerevisiae uracil DNA glycosylase in the suppression of mutagenesis in non-dividing, adenine-starved cells expressing human activation-induced deaminase (AID) gene. Our aim was to further understand the mechanisms preventing starvation-associated mutagenesis in yeast and to explore the consequences of AID gene expression in non-proliferating eukaryotic cells. Genetic control of starvation-induced mutagenesis in many aspects is similar to the control of spontaneous logarithmic phase mutagenesis. Low DNA polymerase fidelity, defects of mismatch repair or post-replication repair lead to the elevation of mutagenesis. Less is known about the role of uracil in DNA. In yeast, the UNG1 gene codes for a uracil DNA glycosylase, which removes uracil from DNA, thus preventing an accumulation of mutations. The UNG1 gene is constitutively expressed at low levels throughout the cell cycle and peaks in late G1/early S phase. We have shown that the wild-type UNG1 allele protects from AID-induced mutations in starved cells to the same extent as it does in logarithmic growth phase cells. This finding implies that the first step in uracil removal by base excision repair (BER) is similar in these two conditions and provides the first data for understanding the role of BER in starvation-associated mutagenesis.

Keywords

Starvation-associated mutagenesis Cytosine deamination Activation-induced deaminase Uracil DNA glycosylase Saccharomyces cerevisiae 

References

  1. Achilli A, Pavlov YI, Matmati N, Casalone E, Morpurgo G, Lucaccioni A, Pavlov YI, Babudri N (2004) The exceptionally high rate of spontaneous mutations in the polymerase delta proof-reading exonuclease deficient S. cerevisiae strains starved for adenine. BMC Genet 5:34–44PubMedCrossRefGoogle Scholar
  2. Babudri N, Pavlov YI, Matmati N, Ludovisi C, Achilli A (2001) Stationary-phase mutations in proofreading exonuclease-deficient strains in the yeast Saccharomyces cerevisiae. Mol Gen Genomics 265:362–366CrossRefGoogle Scholar
  3. Babudri N, Lucaccioni A, Achilli A (2006) Adaptive mutagenesis in the yeast Saccharomyces cerevisiae. Ecol Genet 4:20–28Google Scholar
  4. Baranowska H, Policinska Z, Jachymezyk WY (1995) Effects of the CDC2 gene on adaptive mutation in the yeast Saccharomyces cerevisiae. Curr Genet 28:521–525PubMedCrossRefGoogle Scholar
  5. Basu U, Chaudhuri J, Phan RT, Datta A, Alt FW (2007) Regulation of activation induced deaminase via phosphorylation. Adv Exp Med Biol 596:129–137PubMedGoogle Scholar
  6. Boiteux S, Guillet M (2004) Abasic sites in DNA: repair and biological consequences in Saccharomyces cerevisiae. DNA Repair 3:1–12PubMedCrossRefGoogle Scholar
  7. Bridges BA (1996) Mutation in resting cells: the role of endogenous DNA damage. Cancer Surv 2:155–167Google Scholar
  8. Brooks PJ (2002) DNA repair in neural cells: basic science and clinical implications. Mutat Res 509:93–108PubMedGoogle Scholar
  9. Ceiká P, Vondrejs V, Storchová S (2001) Dissection of the functions of the Saccharomyces cerevisiae RAD6 postreplicative repair group in mutagenesis and UV sensitivity. Genetics 159:953–963Google Scholar
  10. de Yébenes VG, Ramiro AR (2006) Activation-induced deaminase: light and dark sides. Trends Mol Med 12:432–439PubMedCrossRefGoogle Scholar
  11. Halas A, Baranowska H, Policinska Z (2002) The influence of the mismatch-repair system on stationary-phase mutagenesis in the yeast Saccharomyces cerevisiae. Curr Genet 42:140–146PubMedCrossRefGoogle Scholar
  12. Heidenreich E (2007) Adaptive mutation in Saccharomyces cerevisiae. Crit Rev Biochem Mol Biol 42:285–311PubMedCrossRefGoogle Scholar
  13. Heidenreich E, Holzmann V, Eisler H (2004) Polymerase zeta dependency of increased adaptive mutation frequencies in nucleotide excision repair-deficient yeast strains. DNA Repair 3:395–402PubMedCrossRefGoogle Scholar
  14. Heidenreich E, Novotny R, Kneidinger B, Holzmann V, Wintersberger U (2003) Non-homologous end joining as an important mutagenic process in cell cycle-arrested cells. EMBO J 22:2274–2283PubMedCrossRefGoogle Scholar
  15. Johnson LH, Johnson AL (1995) The DNA repair genes RAD54 and UNG1 are cell cycle regulated in budding yeast but MCB promoter elements have no essential role in the DNA damage response. Nucleic Acids Res 23:2147–2152PubMedCrossRefGoogle Scholar
  16. Kavli B, Otterrlei M, Slupphaug G, Krokan HE (2007) Uracil in DNA: general mutagen, but normal intermediate in acquired immunity. DNA Repair 6:505–516PubMedCrossRefGoogle Scholar
  17. Maki H (2002) Origins of spontaneous mutations: specificity and directionality of base-substitutions, frame-shift and sequence-substitution mutagenesis. Annu Rev Genet 36:279–303PubMedCrossRefGoogle Scholar
  18. Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T, Azuma T. Okazaki IM, Honjo T, Chiba T (2007) Helicobacter pilori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med 13:470–476PubMedCrossRefGoogle Scholar
  19. Mayorov VI, Rogozin IB, Adkinson LR, Frahm C, Kunkel TA, Pavlov YI (2005) Expression of human AID in yeast induces mutations in context similar to the context of somatic hypermutation at G-C pairs in immunoglobulin genes. BMC Immunol 6:10–22PubMedCrossRefGoogle Scholar
  20. Neuberger MS, Rada C (2007) Somatic hypermutation: activation-induced deaminase for C/G followed by polymerase eta for A/T. J Exp Med 22:7–10CrossRefGoogle Scholar
  21. Okazaki I, Hiai H, Kakazu N, Yamada S, Muramatsu M, Kinoshita K, Honjo T (2003) Constitutive expression of AID leads to tumorigenesis. J Exp Med 197:1173–1181PubMedCrossRefGoogle Scholar
  22. Okazaki I, Kotani A, Honjo T (2007) Role of AID in tumorigenesis. Adv Immunol 94:245–273PubMedGoogle Scholar
  23. Percudani R, Pavesi A, Ottonello S (1997) Transfer RNA gene redundancy and translesional selection in Saccharomyces cerevisiae. J Mol Biol 268:322–330PubMedCrossRefGoogle Scholar
  24. Petersen-Mahrt SK, Harris RS, Neuberger MS (2002) AID mutates E.coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418: 99–103PubMedCrossRefGoogle Scholar
  25. Pham P, Bransteitter R, Goodman MF (2005) Reward versus risk: DNA cytidine deaminases triggering immunity and diseases. Biochemistry 44:2703–2715PubMedCrossRefGoogle Scholar
  26. Poltoratsky VP, Wilson SH, Kunkel TA, Pavlov YI (2004) Recombinogenic phenotype of human activation-induced cytosine deaminase. J Immunol 172:4308–4313PubMedGoogle Scholar
  27. Ronai D, Iglesias-Ussel MD, Fan M, Li Z, Martin A, Scharff MD (2007) Detection of chromatin-associated single-stranded DNA in regions targeted for somatic hypermutation. J Exp Med 204:181–190PubMedCrossRefGoogle Scholar
  28. Rosche WA, Foster PL (2000) Determining mutation rates in bacterial populations. Methods 20:4–17PubMedCrossRefGoogle Scholar
  29. Shcherbakova PV, Kunkel TA (1999) Mutator phenotypes conferred by MLH1 overexpression and by heterozygosity for mlh1 mutations. Mol Cell Biol 19:3177–3183PubMedGoogle Scholar
  30. Sherman F (1991) Getting started with yeast. Methods Enzymol 194:3–21PubMedCrossRefGoogle Scholar
  31. Shinkura R, Okazaki IM, Muto T, Begum NA, Honjo T (2007) Regulation of AID function in vivo. Adv Exp Med Biol 596:71–81PubMedGoogle Scholar
  32. Storchová Z, Rojas Gil AP, Janderová B, Vondrejs V (1998) The involvement of the RAD6 gene in starvation-induced reverse mutations in Saccharomyces cerevisiae. Mol Gen Genet 258:546–552PubMedCrossRefGoogle Scholar
  33. Townson JL, Chambers AF (2006) Dormancy of solitary metastatic cells. Cell Cycle 5:1744–1750PubMedGoogle Scholar
  34. Unniraman S, Schatz DG (2007) Strand-biased spreading of mutations during somatic hypermutation. Science 317:1227–1230PubMedCrossRefGoogle Scholar
  35. Wagner SD, Neuberger MS (1996) Somatic hypermutation of immunoglobulin genes. Ann Rev Immunol 14:441–457CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Angela Lucaccioni
    • 1
  • Youri I. Pavlov
    • 2
  • Alessandro Achilli
    • 3
  • Nora Babudri
    • 1
  1. 1.Dipartimento di Biologia Cellulare e AmbientaleUniversità di PerugiaPerugiaItaly
  2. 2.Department of Biochemistry and Molecular Biology, and Department of Microbiology and PathologyEppley Institute for Cancer Research, University of Nebraska Medical CenterOmahaUSA
  3. 3.Dipartimento di Genetica e MicrobiologiaUniversità di Pavia, Polo Universitario CravinoPaviaItaly

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