End Resection Initiates Genomic Instability in the Absence of Telomerase

REFERENCES

• Artandi, S. E., S. Chang, S. L. Lee, S. Alson, G. J. Gottlieb, L. Chin, and R. A. DePinho. 2000. Telomere dysfunction promotes nonreciprocal translocations and epithelial cancers in mice. Nature 406: 641–645.
   PubMed Web of Science ®Google Scholar
• Baumann, P., and T. R. Cech. 2001. Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292: 1171–1175.
   PubMed Web of Science ®Google Scholar
• Baumann, P., and T. R. Cech. 2000. Protection of telomeres by the Ku protein in fission yeast. Mol. Biol. Cell 11: 3265–3275.
   PubMedGoogle Scholar
• Blasco, M. A., H.-W. Lee, P. M. Hande, E. Samper, P. M. Lansdorp, R. A. DePinho, and C. W. Greider. 1997. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91: 25–34.
   PubMed Web of Science ®Google Scholar
• Brachmann, C. B., A. Davies, G. J. Cost, E. Caputo, J. Li, P. Hieter, and J. D. Boeke. 1998. Designer deletion strains derived from Saccharomyces cerevisiae S288C: a useful set of strains and plasmids for PCR-mediated gene disruption and other applications. Yeast 14: 115–132.
   PubMed Web of Science ®Google Scholar
• Cahill, D. P., C. Lengauer, J. Yu, G. J. Riggins, J. K. Willson, S. D. Markowitz, K. W. Kinzler, and B. Vogelstein. 1998. Mutations of mitotic checkpoint genes in human cancers. Nature 392: 300–303.
   PubMed Web of Science ®Google Scholar
• Carson, M., and L. Hartwell. 1985. CDC17: an essential gene that prevents telomere elongation in yeast. Cell 42: 249–257.
   PubMedGoogle Scholar
• Chan, S. W.-L., and E. H. Blackburn. 2003. Telomerase and ATM/Tel1p protect telomeres from nonhomologous end joining. Mol. Cell 11: 1379–1387.
   PubMedGoogle Scholar
• Chen, C., and R. D. Kolodner. 1999. Gross chromosomal rearrangements in Saccharomyces cerevisiae replication and recombination defective mutants. Nat. Genet. 23: 81–85.
   PubMed Web of Science ®Google Scholar
• Cheng, T. H., C. R. Chang, P. Joy, S. Yablok, and M. R. Gartenberg. 2000. Controlling gene expression in yeast by inducible site-specific recombination. Nucleic Acids Res. 28: E108.
   PubMedGoogle Scholar
• Craven, R. J., P. W. Greenwell, M. Dominska, and T. D. Petes. 2002. Regulation of genome stability by TEL1 and MEC1, yeast homologs of the mammalian ATM and ATR genes. Genetics 161: 493–507.
   PubMedGoogle Scholar
• DePinho, R. A. 2000. The age of cancer. Nature 408: 248–254.
   PubMed Web of Science ®Google Scholar
• Diede, S. J., and D. E. Gottschling. 2001. Exonuclease activity is required for sequence addition and Cdc13p loading at a de novo telomere. Curr. Biol. 11: 1336–1340.
   PubMedGoogle Scholar
• Dionne, I., and R. J. Wellinger. 1996. Cell cycle-regulated generation of single-stranded G-rich DNA in the absence of telomerase. Proc. Natl. Acad. Sci. USA 93: 13902–13907.
   PubMedGoogle Scholar
• Enomoto, S., L. Glowczewski, and J. Berman. 2002. MEC3, MEC1, and DDC2 are essential components of a telomere checkpoint pathway required for cell cycle arrest during senescence in Saccharomyces cerevisiae. Mol. Biol. Cell 13: 2626–2638.
   PubMedGoogle Scholar
• Espejel, S., S. Franco, S. Rodriguez-Perales, S. D. Bouffler, J. C. Cigudosa, and M. A. Blasco. 2002. Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres. EMBO J. 21: 2207–2219.
   PubMed Web of Science ®Google Scholar
• Esposito, M. S., and J. E. Wagstaff. 1981. Mechanisms of mitotic recombination, p. 341–370. In J. N. Strathern, E. W. Jones, and J. R. Broach (ed.), The molecular biology of the yeast Saccharomyces: life cycle and inheritance. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.
   Google Scholar
• Feldser, D. M., J. A. Hackett, and C. W. Greider. 2003. Telomere dysfunction and the initiation of genome instability. Nat. Rev. Cancer. 3: 623–627.
   PubMed Web of Science ®Google Scholar
• Ferreira, M. G., and J. P. Cooper. 2001. The fission yeast Taz1 protein protects chromosomes from Ku-dependent end-to-end fusions. Mol. Cell 7: 55–63.
   PubMedGoogle Scholar
• Garvik, B., M. Carson, and L. Hartwell. 1995. Single-stranded DNA arising at telomeres in cdc13 mutants may constitute a specific signal for the RAD9 checkpoint. Mol. Cell. Biol. 15: 6128–6138.
   PubMed Web of Science ®Google Scholar
• Gerring, S. L., C. Connelly, and P. Hieter. 1991. Positional mapping of genes by chromosome blotting and chromosome fragmentation. Methods Enzymol. 194: 57–77.
   PubMedGoogle Scholar
• Gisselsson, D., T. Jonson, A. Petersen, B. Strombeck, P. Dal Cin, M. Hoglund, F. Mitelman, F. Mertens, and N. Mandahl. 2001. Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc. Natl. Acad. Sci. USA 98: 12683–12688.
   PubMed Web of Science ®Google Scholar
• Goldstein, A. L., and J. H. McCusker. 1999. Three new dominant drug resistance cassettes for gene disruption in Saccharomyces cerevisiae. Yeast 15: 1541–1553.
   PubMed Web of Science ®Google Scholar
• Greenberg, R., L. Chin, A. Femino, K.-H. Lee, G. Gottlieb, R. Singer, C. W. Greider, and R. A. DePinho. 1999. Short dysfunctional telomeres impair tumorigenesis in the INK4aΔ2/3−/− cancer prone mouse. Cell 97: 515–525.
   PubMed Web of Science ®Google Scholar
• Greider, C. W., and E. H. Blackburn. 1985. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43: 405–413.
   PubMed Web of Science ®Google Scholar
• Guldener, U., S. Heck, T. Fielder, J. Beinhauer, and J. H. Hegemann. 1996. A new efficient gene disruption cassette for repeated use in budding yeast. Nucleic Acids Res. 24: 2519–2524.
   PubMed Web of Science ®Google Scholar
• Hackett, J. A., D. M. Feldser, and C. W. Greider. 2001. Telomere dysfunction increases mutation rate and genomic instability. Cell 106: 275–286.
   PubMed Web of Science ®Google Scholar
• Hackett, J. A., and C. W. Greider. 2002. Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis. Oncogene 21: 619–626.
   PubMed Web of Science ®Google Scholar
• Harley, C. B. 1990. Aging in cultured human fibroblasts. Methods Mol. Biol. 5: 25–32.
   PubMedGoogle Scholar
• Hemann, M. T., M. A. Strong, L. Y. Hao, and C. W. Greider. 2001. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107: 67–77.
   PubMed Web of Science ®Google Scholar
• Hiraoka, M., K. Watanabe, K. Umezu, and H. Maki. 2000. Spontaneous loss of heterozygosity in diploid Saccharomyces cerevisiae cells. Genetics 156: 1531–1548.
   PubMedGoogle Scholar
• IJpma, A., and C. W. Greider. 2003. Short telomeres induce a DNA damage response in Saccharomyces cerevisiae. Mol. Biol. Cell 14: 987–1001.
   PubMedGoogle Scholar
• Ira, G., and J. E. Haber. 2002. Characterization of RAD51-independent break-induced replication that acts preferentially with short homologous sequences. Mol. Cell. Biol. 18: 6384–6392.
   Google Scholar
• Ivanov, E. L., and J. E. Haber. 1995. RAD1 and RAD10, but not other excision repair genes, are required for double-strand break-induced recombination in Saccharomyces cerevisiae. Mol. Cell. Biol. 15: 2245–2251.
   PubMedGoogle Scholar
• Ivanov, E. L., N. Sugawara, C. I. White, F. Fabre, and J. E. Haber. 1994. Mutations in XRS2 and RAD50 delay but do not prevent mating-type switching in Saccharomyces cerevisiae. Mol. Cell. Biol. 14: 3414–3425.
   PubMedGoogle Scholar
• Kraus, E., W. Y. Leung, and J. E. Haber. 2001. Break-induced replication: a review and an example in budding yeast. Proc. Natl. Acad. Sci. USA 98: 8255–8262.
   PubMed Web of Science ®Google Scholar
• Le, S., J. K. Moore, J. E. Haber, and C. W. Greider. 1999. RAD51 and RAD50 define two pathways that collaborate to maintain telomeres in the absence of telomerase. Genetics 152: 143–152.
   PubMed Web of Science ®Google Scholar
• Lea, D. E., and C. A. Coulson. 1949. The distribution of the numbers of mutants in bacterial populations. J. Genet. 49: 264–285.
   PubMed Web of Science ®Google Scholar
• Lee, S. E., J. K. Moore, A. Holmes, K. Umezu, R. D. Kolodner, and J. E. Haber. 1998. Saccharomyces Ku70, Mre11/Rad50, and RPA proteins regulate adaptation to G2/M arrest after DNA damage. Cell 94: 399–409.
   PubMed Web of Science ®Google Scholar
• Lendvay, T. S., D. K. Morris, J. Sah, B. Balasubramanian, and V. Lundblad. 1996. Senescence mutants of Saccharomyces cerevisiae with a defect in telomere replication identify three additional EST genes. Genetics 144: 1399–1412.
   PubMed Web of Science ®Google Scholar
• Lengauer, C., K. W. Kinzler, and B. Vogelstein. 1998. Genetic instabilities in human cancers. Nature 396: 643–649.
   PubMed Web of Science ®Google Scholar
• Lewis, L. K., G. Karthikeyan, J. W. Westmoreland, and M. A. Resnick. 2002. Differential suppression of DNA repair deficiencies of yeast rad50, mre11 and xrs2 mutants by EXO1 and TLC1 (the RNA component of telomerase). Genetics 160: 49–62.
   PubMedGoogle Scholar
• Liti, G., and E. J. Louis. 2003. NEJ1 prevents NHEJ-dependent telomere fusions in yeast without telomerase. Mol. Cell 11: 1373–1378.
   PubMed Web of Science ®Google Scholar
• Lundblad, V., and E. H. Blackburn. 1993. An alternative pathway for yeast telomere maintenance rescues est1− senescence. Cell 73: 347–360.
   PubMed Web of Science ®Google Scholar
• Lundblad, V., and J. W. Szostak. 1989. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57: 633–643.
   PubMed Web of Science ®Google Scholar
• Lydall, D., and T. Weinert. 1995. Yeast checkpoint genes in DNA damage processing: implications for repair and arrest. Science 270: 1488–1491.
   PubMed Web of Science ®Google Scholar
• Malkova, A., E. L. Ivanov, and J. E. Haber. 1996. Double-strand break repair in the absence of RAD51 in yeast: a possible role for break-induced DNA replication. Proc. Natl. Acad. Sci. USA 93: 7131–7136.
   PubMed Web of Science ®Google Scholar
• Mangahas, J. L., M. K. Alexander, L. L. Sandell, and V. A. Zakian. 2001. Repair of chromosome ends after telomere loss in Saccharomyces. Mol. Biol. Cell 12: 4078–4089.
   PubMedGoogle Scholar
• Maringele, L., and D. Lydall. 2002. EXO1-dependent single-stranded DNA at telomeres activates subsets of DNA damage and spindle checkpoint pathways in budding yeast yku70Δ mutants. Genes Dev. 16: 1919–1933.
   PubMed Web of Science ®Google Scholar
• Maser, R. S., and R. A. DePinho. 2002. Connecting chromosomes, crisis, and cancer. Science 297: 565–569.
   PubMed Web of Science ®Google Scholar
• McClintock, B. 1941. The stability of broken ends of chromosomes in Zea mays. Genetics 26: 234–282.
   PubMedGoogle Scholar
• Morrow, D. M., C. Connelly, and P. Hieter. 1997. “Break copy” duplication: a model for chromosome fragment formation in Saccharomyces cerevisiae. Genetics 147: 371–382.
   PubMed Web of Science ®Google Scholar
• Myung, K., C. Chen, and R. D. Kolodner. 2001. Multiple pathways cooperate in the suppression of genome instability in Saccharomyces cerevisiae. Nature 411: 1073–1076.
   PubMedGoogle Scholar
• Nakamura, T. M., J. P. Cooper, and T. R. Cech. 1998. Two modes of survival of fission yeast without telomerase. Science 282: 493–496.
   PubMed Web of Science ®Google Scholar
• Parenteau, J., and R. J. Wellinger. 1999. Accumulation of single-stranded DNA and destabilization of telomeric repeats in yeast mutant strains carrying a deletion of RAD27. Mol. Cell. Biol. 19: 4143–4152.
   PubMedGoogle Scholar
• Pellicioli, A., S. E. Lee, C. Lucca, M. Foiani, and J. E. Haber. 2001. Regulation of Saccharomyces Rad53 checkpoint kinase during adaptation from DNA damage-induced G2/M arrest. Mol. Cell 7: 293–300.
   PubMed Web of Science ®Google Scholar
• Riha, K., and D. E. Shippen. 2003. Ku is required for telomeric C-rich strand maintenance but not for end-to-end chromosome fusions in Arabidopsis. Proc. Natl. Acad. Sci. USA 100: 611–615.
   PubMedGoogle Scholar
• Rose, M. D., W. F., and P. Hieter. 1990. Methods in Yeast Genetics. Cold Spring Harbor Laboratory Press.
   Google Scholar
• Rudolph, K. L., S. Chang, H.-W. Lee, M. Blasco, G. Gottlieb, C. W. Greider, and R. A. DePinho. 1999. Longevity, stress response, and cancer in aging telomerase deficient mice. Cell 96: 701–712.
   PubMed Web of Science ®Google Scholar
• Rudolph, K. L., M. Millard, M. W. Bosenberg, and R. A. DePinho. 2001. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat. Genet. 28: 155–159.
   PubMed Web of Science ®Google Scholar
• Siede, W., A. S. Friedberg, and E. C. and Friedberg. 1993. Evidence that the Rad1 and Rad10 proteins of Saccharomyces cerevisiae participate as a complex in nucleotide excision repair of UV radiation damage. J. Bacteriol. 175: 6345–6347.
   PubMedGoogle Scholar
• Smogorzewska, A., J. Karlseder, H. Holtgreve-Grez, A. Jauch, and T. de Lange. 2002. DNA ligase IV-dependent NHEJ of deprotected mammalian telomeres in G1 and G2. Curr. Biol. 12: 1635–1644.
   PubMed Web of Science ®Google Scholar
• Sugawara, N., and J. E. Haber. 1992. Characterization of double-strand break-induced recombination: homology requirements and single-stranded DNA formation. Mol. Cell. Biol. 12: 563–575.
   PubMedGoogle Scholar
• Thiagalingam, S., S. Laken, J. K. Willson, S. D. Markowitz, K. W. Kinzler, B. Vogelstein, and C. Lengauer. 2001. Mechanisms underlying losses of heterozygosity in human colorectal cancers. Proc. Natl. Acad. Sci. USA 98: 2698–2702.
   PubMedGoogle Scholar
• Tishkoff, D. X., A. L. Boerger, P. Bertrand, N. Filosi, G. M. Gaida, M. F. Kane, and R. D. Kolodner. 1997. Identification and characterization of Saccharomyces cerevisiae EXO1, a gene encoding an exonuclease that interacts with MSH2. Proc. Natl. Acad. Sci. USA 94: 7487–7492.
   PubMed Web of Science ®Google Scholar
• Tsubouchi, H., and H. Ogawa. 2000. Exo1 roles for repair of DNA double-strand breaks and meiotic crossing over in Saccharomyces cerevisiae. Mol. Biol. Cell 11: 2221–2233.
   PubMed Web of Science ®Google Scholar
• Tsukamoto, Y., A. K. Taggart, and V. A. Zakian. 2001. The role of the Mre11-Rad50-Xrs2 complex in telomerase-mediated lengthening of Saccharomyces cerevisiae telomeres. Curr. Biol. 11: 1328–1335.
   PubMed Web of Science ®Google Scholar
• Umezu, K., M. Hiraoka, M. Mori, and H. Maki. 2002. Structural analysis of aberrant chromosomes that occur spontaneously in diploid Saccharomyces cerevisiae: retrotransposon Ty1 plays a crucial role in chromosomal rearrangements. Genetics 160: 97–110.
   PubMedGoogle Scholar
• van Steensel, B., A. Smogorzewska, and T. de Lange. 1998. TRF2 protects human telomeres from end-to-end fusions. Cell 92: 401–413.
   PubMed Web of Science ®Google Scholar
• Vaze, M. B., A. Pellicioli, S. E. Lee, G. Ira, G. Liberi, A. Arbel-Eden, M. Foiani, and J. E. Haber. 2002. Recovery from checkpoint-mediated arrest after repair of a double-strand break requires Srs2 helicase. Mol. Cell 10: 373–385.
   PubMed Web of Science ®Google Scholar
• Weinert, T. A., and L. H. Hartwell. 1993. Cell cycle arrest of cdc mutants and specificity of the RAD9 checkpoint. Genetics 134: 63–80.
   PubMed Web of Science ®Google Scholar
• Weinert, T. A., and L. H. Hartwell. 1988. The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. Science 241: 317–322.
   PubMed Web of Science ®Google Scholar
• Winzeler, E. A., D. D. Shoemaker, A. Astromoff, H. Liang, K. Anderson, B. Andre, R. Bangham, R. Benito, J. D. Boeke, H. Bussey, A. M. Chu, C. Connelly, K. Davis, F. Dietrich, S. W. Dow, M. El Bakkoury, F. Foury, S. H. Friend, E. Gentalen, G. Giaever, J. H. Hegemann, T. Jones, M. Laub, H. Liao, R. W. Davis, et al. 1999. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285: 901–906.
   PubMed Web of Science ®Google Scholar
• Yu, X., and A. Gabriel. 1999. Patching broken chromosomes with extranuclear cellular DNA. Mol. Cell 4: 873–881.
   PubMedGoogle Scholar
• Zakian, V. A. 1989. Structure and function of telomeres. Annu. Rev. Genet. 23: 579–604.
   PubMed Web of Science ®Google Scholar