Genome instability: A mechanistic view of its causes and consequences

Nature Reviews Genetics

Volumn 9, Issue 3, 2008, Pages 204-217

  Aguilera, Andrés ^a   Gómez González, Belén ^a  

^a UNIVERSITY OF SEVILLE   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

CELL CYCLE S PHASE; CHROMATIN ASSEMBLY AND DISASSEMBLY; CHROMOSOMAL INSTABILITY; CHROMOSOME REARRANGEMENT; DNA SEQUENCE; DNA STRAND BREAKAGE; DNA SYNTHESIS; DNA TRANSCRIPTION; GENE AMPLIFICATION; GENE LOCUS; GENE MUTATION; GENE REPLICATION; GENETIC DISORDER; GENOMIC INSTABILITY; HUMAN; MISMATCH REPAIR; NONHUMAN; PRIORITY JOURNAL; REVIEW;

ANIMALS; DNA BREAKS; DNA REPLICATION; EVOLUTION, MOLECULAR; GENOMIC INSTABILITY; HUMANS; IMMUNOGLOBULIN CLASS SWITCHING;

EID: 39449096135     PISSN: 14710056     EISSN: 14710064     Source Type: Journal    
DOI: 10.1038/nrg2268     Document Type: Review

References (153)

1. Maizels, N. Immunoglobulin gene diversification. Annu. Rev. Genet. 39, 23-46 (2005).
2. McMurray, M. A. & Gottschling, D. E. An age-induced switch to a hyper-recombinational state. Science 301, 1908-1911 (2003). This paper describes a strong increase in genomic instability that is linked to ageing in the budding yeast, S. cerevisiae. This constitutes a rational explanation for the association of high cancer risk with age in mammals.
3. Draviam, V. M., Xie, S. & Sorger, P. K. Chromosome segregation and genomic stability. Curr. Opin. Genet. Dev. 14, 120-125 (2004).
4. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907-913 (2005). This paper shows that the DNA-damage response is activated in a panel of human lung hyperplasias, whereas its inactivation leads to malignant transformation, pointing to a role of checkpoints as a natural anticancer barrier.
5. Friedberg, E. C. et al. DNA Repair and Mutagenesis 461-750 (American Society For Microbiology Press, Washington DC, 2006).
6. Myung, K., Datta, A. & Kolodner, R. D. Suppression of spontaneous chromosomal rearrangements by S phase checkpoint functions in Saccharomyces cerevisiae. Cell 104, 397-408 (2001).
7. Myung, K. & Kolodner, R. D. Suppression of genome instability by redundant S-phase checkpoint pathways in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 99, 4500-4507 (2002).
8. Rudolph, C. J., Upton, A. L. & Lloyd, R. G. Replication fork stalling and cell cycle arrest in UV-irradiated Escherichia coli. Genes Dev. 21, 668-681 (2007).
9. Cobb, J. A. et al. Replisome instability, fork collapse, and gross chromosomal rearrangements arise synergistically from Mec1 kinase and RecQ helicase mutations. Genes Dev. 19, 3055-3069 (2005).
10. Sogo, J. M., Lopes, M. & Foiani, M. Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects. Science 297, 599-602 (2002). This paper presents electron microscopy visualization of RF intermediates in S. cerevisiae rad53 checkpoint mutants under replication stress induced by hydroxyurea, revealing long ssDNA accumulation and hemi-replicated molecules. HJ structures are observed as a consequence of fork reversal.
11. Cortes-Ledesma, F. & Aguilera, A. Double-strand breaks arising by replication through a nick are repaired by cohesin-dependent sister-chromatid exchange. EMBO Rep. 7, 919-926 (2006).
12. Pages, V. & Fuchs, R. P. Uncoupling of leading- and lagging-strand DNA replication during lesion bypass in vivo. Science 300, 1300-1303 (2003).
13. Lopes, M., Foiani, M. & Sogo, J. M. Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions. Mol. Cell 21, 15-27 (2006).
14. Cordeiro-Stone, M., Makhov, A. M., Zaritskaya, L. S. & Griffith, J. D. Analysis of DNA replication forks encountering a pyrimidine dimer in the template to the leading strand. J. Mol. Biol. 289, 1207-1218 (1999).
15. Higgins, N. P., Kato, K. & Strauss, B. A model for replication repair in mammalian cells. J. Mol. Biol. 101, 417-425 (1976).
16. Seigneur, M., Bidnenko, V., Ehrlich, S. D. & Michel, B. RuvAB acts at arrested replication forks. Cell 95, 419-430 (1998). In this paper, the presence of linear DNA as evidence of DSBs in E. coli together with genetic data are used as a demonstration of the occurrence of fork reversal to a HJ structure in arrested RFs.
17. Heller, R. C. & Marians, K. J. Replisome assembly and the direct restart of stalled replication forks. Nature Rev. Mol. Cell Biol. 7, 932-943 (2006).
18. Heller, R. C. & Marians, K. J. Replication fork reactivation downstream of a blocked nascent leading strand. Nature 439, 557-562 (2006).
19. Berdichevsky, A., Izhar, L. & Livneh, Z. Error-free recombinational repair predominates over mutagenic translesion replication in E. coli. Mol. Cell 10, 917-924 (2002).
20. Fabre, F., Chan, A., Heyer, W. D. & Gangloff, S. 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. USA 99, 16887-16892 (2002).
21. Klein, H. L. & Petes, T. D. Intrachromosomal gene conversion in yeast. Nature 289, 144-148 (1981).
22. Jackson, J. A. & Fink, G. R. Gene conversion between duplicated genetic elements in yeast. Nature 292, 306-311 (1981).
23. Aguilera, A. & Klein, H. L. Genetic control of intrachromosomal recombination in Saccharomyces cerevisiae. I. Isolation and genetic characterization of hyper-recombination mutations. Genetics 119, 779-790 (1988).
24. Chen, C., Umezu, K. & Kolodner, R. D. Chromosomal rearrangements occur in S. cerevisiae rfa1 mutator mutants due to mutagenic lesions processed by double-strand-break repair. Mol. Cell 2, 9-22 (1998).
25. Chen, C. & Kolodner, R. D. Gross chromosomal rearrangements in Saccharomyces cerevisiae replication and recombination defective mutants. Nature Genet. 23, 81-85 (1999).
26. Marinus, M. G. & Konrad, E. B. Hyper-recombination in dam mutants of Escherichia coli K-12. Mol. Gen. Genet. 149, 273-277 (1976).
27. Hartwell, L. H. & Smith, D. Altered fidelity of mitotic chromosome transmission in cell cycle mutants of S. cerevisiae. Genetics 110, 381-395 (1985).
28. Zieg, J., Maples, V. F. & Kushner, S. R. Recombinant levels of Escherichia coli K-12 mutants deficient in various replication, recombination or repair genes. J. Bacteriol. 134, 958-966 (1978).
29. Tishkoff, D. X., Filosi, N., Gaida, G. M. & Kolodner, R. D. A novel mutation avoidance mechanism dependent on S. cerevisiae Rad27 is distinct from DNA mismatch repair. Cell 88, 253-263 (1997).
30. Prado, F., Cortes-Ledesma, F. & Aguilera, A. The absence of the yeast chromatin assembly factor Asf1 increases genomic instability and sister chromatid exchange. EMBO Rep. 5, 497-502 (2004).
31. Myung, K., Pennaneach, V., Kats, E. S. & Kolodner, R. D. Saccharomyces cerevisiae chromatin-assembly factors that act during DNA replication function in the maintenance of genome stability. Proc. Natl Acad. Sci. USA 100, 6640-6645 (2003).
32. Gangloff, S., McDonald, J. P., Bendixen, C., Arthur, L. & Rothstein, R. The yeast type I topoisomerase Top3 interacts with Sgs1, a DNA helicase homolog: a potential eukaryotic reverse gyrase. Mol. Cell Biol. 14, 8391-8398 (1994).
33. Lambert, S., Watson, A., Sheedy, D. M., Martin, B. & Carr, A. M. Gross chromosomal rearrangements and elevated recombination at an inducible site-specific replication fork barrier. Cell 121, 689-702 (2005).
34. Prado, F. & Aguilera, A. Impairment of replication fork progression mediates RNA polII transcription-associated recombination. EMBO J. 24, 1267-1276 (2005).
35. Takeuchi, Y., Horiuchi, T. & Kobayashi, T. Transcription-dependent recombination and the role of fork collision in yeast rDNA. Genes Dev. 17, 1497-1506 (2003).
36. Myung, K., Chen, C. & Kolodner, R. D. Multiple pathways cooperate in the suppression of genome instability in Saccharomyces cerevisiae. Nature 411, 1073-1076 (2001). In this paper, genetic analyses serve to define three groups of suppressors of the formation of GCRs in S. cerevisiae: S-phase checkpoints, recombination factors and proteins that are involved in de novo telomere addition.
37. Ivessa, A. S. et al. The Saccharomyces cerevisiae helicase Rrm3p facilitates replication past nonhistone protein-DNA complexes. Mol. Cell 12, 1525-1536 (2003).
38. Schmidt, K. H. & Kolodner, R. D. Suppression of spontaneous genome rearrangements in yeast DNA helicase mutants. Proc. Natl Acad. Sci. USA 103, 18196-18201 (2006).
39. Lengronne, A. & Schwob, E. The yeast CDK inhibitor Sic1 prevents genomic instability by promoting replication origin licensing in late G1. Mol. Cell 9, 1067-1078 (2002).
40. Mieczkowski, P. A., Mieczkowska, J. O., Dominska, M. & Petes, T. D. Genetic regulation of telomere-telomere fusions in the yeast Saccharomyces cerevisae. Proc. Natl Acad. Sci. USA 100, 10854-10859 (2003).
41. Wang, Y. et al. Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice. Nature Genet. 37, 750-755 (2005).
42. Shima, N. et al. A viable allele of Mcm4 causes chromosome instability and mammary adenocarcinomas in mice. Nature Genet. 39, 93-98 (2007). Together with reference 41, this paper demonstrates the existence of GIN in replication mutants (Rpa1 and Mcm4) of mice, indicating that replication impairment is a source of GIN in mammals.
43. Schulz, V. P. & Zakian, V. A. The Saccharomyces PIF1 DNA helicase inhibits telomere elongation and de novo telomere formation. Cell 76, 145-155 (1994).
44. Kobayashi, T. & Ganley, A. R. Recombination regulation by transcription-induced cohesin dissociation in rDNA repeats. Science 309, 1581-1584 (2005).
45. De Piccoli, G. et al. Smc5-Smc6 mediate DNA double-strand-break repair by promoting sister-chromatid recombination. Nature Cell Biol. 8, 1032-1034 (2006).
46. Sutherland, G. R. Fragile sites on human chromosomes: demonstration of their dependence on the type of tissue culture medium. Science 197, 265-266 (1977).
47. Durkin, S. G. & Glover, T. W. Chromosome fragile sites. Annu. Rev. Genet. (2007).
48. Yunis, J. J. & Soreng, A. L. Constitutive fragile sites and cancer. Science 226, 1199-1204 (1984).
49. Mirkin, S. M. Expandable DNA repeats and human disease. Nature 447, 932-940 (2007).
50. Shiraishi, T. et al. Sequence conservation at human and mouse orthologous common fragile regions, FRA3B/FHIT and Fra14A2/Fhit. Proc. Natl Acad. Sci. USA 98, 5722-5727 (2001).
51. Cha, R. S. & Kleckner, N. ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones. Science 297, 602-606 (2002).
52. Lemoine, F. J., Degtyareva, N. P., Lobachev, K. & Petes, T. D. Chromosomal translocations in yeast induced by low levels of DNA polymerase a model for chromosome fragile sites. Cell 120, 587-598 (2005). In this paper, the elimination of Mec1 in budding yeast leads to RF collapse in specific regions of the genome, named replication slow zones. Reduced levels of the replicative polymerase α result in translocations and chromosome loss in a region containing two inverted copies of Ty. References 51 and 52 provide evidence of the existence of fragile sites in yeast with similar features to those of mammals.
53. Raveendranathan, M. et al. Genome-wide replication profiles of S-phase checkpoint mutants reveal fragile sites in yeast. EMBO J. 25, 3627-3639 (2006).
54. Samadashwily, G. M., Raca, G. & Mirkin, S. M. Trinucleotide repeats affect DNA replication in vivo. Nature Genet. 17, 298-304 (1997). In this paper, electrophoretic analyses of RF progression in an E. coli plasmid that contains trinucleotide repeats show that RF stalling depends on repeat length and orientation with respect to replication origins, suggesting that the formation of unusual DNA structures in the lagging-strand template is responsible for replication blockage and repeat expansions.
55. Freudenreich, C. H., Kantrow, S. M. & Zakian, V. A. Expansion and length-dependent fragility of CTG repeats in yeast. Science 279, 853-856 (1998).
56. Callahan, J. L., Andrews, K. J., Zakian, V. A. & Freudenreich, C. H. Mutations in yeast replication proteins that increase CAG/CTG expansions also increase repeat fragility. Mol. Cell Biol. 23, 7849-7860 (2003).
57. Zhang, H. & Freudenreich, C. H. An AT-rich sequence in human common fragile site FRA16D causes fork stalling and chromosome breakage in S. cerevisiae. Mol. Cell 27, 367-379 (2007). In this paper, analysis of the replication intermediates formed in the human common fragile site FRA16D placed into a yeast artificial chromosome reveals that RF stalling and DSBs are responsible for the fragility of these sites.
58. Gacy, A. M., Goellner, G., Juranic, N., Macura, S. & McMurray, C. T. Trinucleotide repeats that expand in human disease form hairpin structures in vitro. Cell 81, 533-540 (1995).
59. 15 forms a heat-stable hairpin containing Gsyn.Ganti base pairs. Biochemistry 34, 12803-12811 (1995).
60. Wells, R. D. Molecular basis of genetic instability of triplet repeats. J. Biol. Chem. 271, 2875-2878 (1996).
61. Moore, H., Greenwell, P. W., Liu, C. P., Arnheim, N. & Petes, T. D. Triplet repeats form secondary structures that escape DNA repair in yeast. Proc. Natl Acad. Sci. USA 96, 1504-1509 (1999).
62. Manley, K., Shirley, T. L., Flaherty, L. & Messer, A. Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nature Genet. 23, 471-473 (1999).
63. Richard, G. F., Goellner, G. M., McMurray, C. T. & Haber, J. E. Recombination-induced CAG trinucleotide repeat expansions in yeast involve the Mre11-Rad50-Xrs2 complex. EMBO J. 19, 2381-2390 (2000).
64. Leach, D. R., Okely, E. A. & Pinder, D. J. Repair by recombination of DNA containing a palindromic sequence. Mol. Microbiol. 26, 597-606 (1997).
65. Lobachev, K. S., Gordenin, D. A. & Resnick, M. A. The Mre11 complex is required for repair of hairpin-capped double-strand breaks and prevention of chromosome rearrangements. Cell 108, 183-193 (2002).
66. Kang, S., Jaworski, A., Ohshima, K. & Wells, R. D. Expansion and deletion of CTG repeats from human disease genes are determined by the direction of replication in E. coli. Nature Genet. 10, 213-218 (1995).
67. Freudenreich, C. H., Stavenhagen, J. B. & Zakian, V. A. Stability of a CTG/CAG trinucleotide repeat in yeast is dependent on its orientation in the genome. Mol. Cell Biol. 17, 2090-2098 (1997).
68. Maurer, D. J., O'Callaghan, B. L. & Livingston, D. M. Orientation dependence of trinucleotide CAG repeat instability in Saccharomyces cerevisiae. Mol. Cell Biol. 16, 6617-6622 (1996).
69. Schweitzer, J. K. & Livingston, D. M. The effect of DNA replication mutations on CAG tract stability in yeast. Genetics 152, 953-963 (1999).
70. Lahiri, M., Gustafson, T. L., Majors, E. R. & Freudenreich, C. H. Expanded CAG repeats activate the DNA damage checkpoint pathway. Mol. Cell 15, 287-293 (2004).
71. Spiro, C. et al. Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats. Mol. Cell 4, 1079-1085 (1999).
72. Glover, T. W., Berger, C., Coyle, J. & Echo, B. DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum. Genet. 67, 136-142 (1984).
73. Casper, A. M., Nghiem, P., Arlt, M. F. & Glover, T. W. ATR regulates fragile site stability. Cell 111, 779-789 (2002). This paper demonstrates the role of the replication checkpoint kinase ATR in the maintenance of fragile site stability.
74. Admire, A. et al. Cycles of chromosome instability are associated with a fragile site and are increased by defects in DNA replication and checkpoint controls in yeast. Genes Dev. 20, 159-173 (2006).
75. Pelletier, R., Krasilnikova, M. M., Samadashwily, G. M., Lahue, R. & Mirkin, S. M. Replication and expansion of trinucleotide repeats in yeast. Mol. Cell Biol. 23, 1349-1357 (2003).
76. Krasilnikova, M. M. & Mirkin, S. M. Replication stalling at Friedreich's ataxia (GAA)n repeats in vivo. Mol. Cell Biol. 24, 2286-2295 (2004).
77. Schwartz, M. et al. Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability. Genes Dev. 19, 2715-2726 (2005).
78. Aguilera, A. The connection between transcription and genomic instability. EMBO J. 21, 195-201 (2002).
79. Ikeda, H. & Matsumoto, T. Transcription promotes recA-independent recombination mediated by DNA-dependent RNA polymerase in Escherichia coli. Proc. Natl Acad. Sci. USA 76, 4571-4575 (1979).
80. Voelkel-Meiman, K., Keil, R. L. & Roeder, G. S. Recombination- stimulating sequences in yeast ribosomal DNA correspond to sequences regulating transcription by RNA polymerase I. Cell 48, 1071-1079 (1987).
81. Thomas, B. J. & Rothstein, R. Elevated recombination rates in transcriptionally active DNA. Cell 56, 619-630 (1989).
82. Grimm, C., Schaer, P., Munz, P. & Kohli, J. The strong ADH1 promoter stimulates mitotic and meiotic recombination at the ADE6 gene of Schizosaccharomyces pombe. Mol. Cell Biol. 11, 289-298 (1991).
83. Dul, J. L. & Drexler, H. Transcription stimulates recombination. II. Generalized transduction of Escherichia coli by phages T1 and T4. Virology 162, 471-477 (1988).
84. Nickoloff, J. A. & Reynolds, R. J. Transcription stimulates homologous recombination in mammalian cells. Mol. Cell Biol. 10, 4837-4845 (1990).
85. Brock, R. D. Differential mutation of the beta-galactosidase gene of Escherichia coli. Mutat. Res. 11, 181-186 (1971).
86. Herman, R. K. & Dworkin, N. B. Effect of gene induction on the rate of mutagenesis by ICR-191 in Escherichia coli. J. Bacteriol. 106, 543-550 (1971).
87. Beletskii, A. & Bhagwat, A. S. Transcription-induced mutations: increase in C to T mutations in the nontranscribed strand during transcription in Escherichia coli. Proc. Natl Acad. Sci. USA 93, 13919-13924 (1996).
88. Datta, A. & Jinks-Robertson, S. Association of increased spontaneous mutation rates with high levels of transcription in yeast. Science 268, 1616-1619 (1995).
89. Green, P., Ewing, B., Miller, W., Thomas, P. J. & Green, E. D. Transcription-associated mutational asymmetry in mammalian evolution. Nature Genet. 33, 514-517 (2003).
90. Lindahl, T. Instability and decay of the primary structure of DNA. Nature 362, 709-715 (1993).
91. Frederico, L. A., Kunkel, T. A. & Shaw, B. R. A sensitive genetic assay for the detection of cytosine deamination: determination of rate constants and the activation energy. Biochemistry 29, 2532-2537 (1990).
92. Kim, N., Abdulovic, A. L., Gealy, R., Lippert, M. J. & Jinks-Robertson, S. Transcription-associated mutagenesis in yeast is directly proportional to the level of gene expression and influenced by the direction of DNA replication. DNA Repair (Amst) 6, 1285-1296 (2007).
93. Garcia-Rubio, M., Huertas, P., Gonzalez-Barrera, S. & Aguilera, A. Recombinogenic effects of DNA-damaging agents are synergistically increased by transcription in Saccharomyces cerevisiae. New insights into transcription-associated recombination. Genetics 165, 457-466 (2003).
94. - strain of Escherichia coli. Mol. Gen. Genet. 209, 78-82 (1987).
95. Skandalis, A., Ford, B. N. & Glickman, B. W. Strand bias in mutation involving 5-methylcytosine deamination in the human HPRT gene. Mutat. Res. 314, 21-26 (1994).
96. Drolet, M. et al. Overexpression of RNase H partially complements the growth defect of an Escherichia coli delta topA mutant: R-loop formation is a major problem in the absence of DNA topoisomerase I. Proc. Natl Acad. Sci. USA 92, 3526-3530 (1995).
97. Masse, E. & Drolet, M. Escherichia coli DNA topoisomerase I inhibits R-loop formation by relaxing transcription-induced negative supercoiling. J. Biol. Chem. 274, 16659-16664 (1999).
98. Huertas, P. & Aguilera, A. Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol. Cell 12, 711-721 (2003). This paper shows that hyper-recombinant yeast THO mutants that are defective in mRNP biogenesis allow the co-transcriptional formation of R loops at particular DNA sequences.
99. Li, X. & Manley, J. L. Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122, 365-378 (2005).
100. Aguilera, A. Cotranscriptional mRNP assembly: from the DNA to the nuclear pore. Curr. Opin. Cell Biol. 17, 242-250 (2005).
101. Keene, J. D. RNA regulons: coordination of post-transcriptional events. Nature Rev. Genet. 8, 533-543 (2007).
102. Prado, F., Piruat, J. I. & Aguilera, A. Recombination between DNA repeats in yeast hpr1 delta cells is linked to transcription elongation. EMBO J. 16, 2826-2835 (1997).
103. Luna, R. et al. Interdependence between transcription and mRNP processing and export, and its impact on genetic stability. Mol. Cell 18, 711-722 (2005).
104. Gallardo, M., Luna, R., Erdjument-Bromage, H., Tempst, P. & Aguilera, A. Nab2p and the Thp1p-Sac3p complex functionally interact at the interface between transcription and mRNA metabolism. J. Biol. Chem. 278, 24225-24232 (2003).
105. Fan, H. Y., Merker, R. J. & Klein, H. L. High-copy-number expression of Sub2p, a member of the RNA helicase superfamily, suppresses hpr1-mediated genomic instability. Mol. Cell Biol. 21, 5459-5470 (2001).
106. Gomez-Gonzalez, B. & Aguilera, A. Activation-induced cytidine deaminase action is strongly stimulated by mutations of the THO complex. Proc. Natl Acad. Sci. USA 104, 8409-8414 (2007).
107. Yu, K., Chedin, F., Hsieh, C. L., Wilson, T. E. & Lieber, M. R. R-loops at immunoglobulin class switch regions in the chromosomes of stimulated B cells. Nature Immunol. 4, 442-451 (2003). This paper provides a molecular demonstration of the existence of R loops in the Ig S regions in vivo, which are important for CSR.
108. Wierdl, M., Greene, C. N., Datta, A., Jinks-Robertson, S. & Petes, T. D. Destabilization of simple repetitive DNA sequences by transcription in yeast. Genetics 143, 713-721 (1996).
109. Krasilnikova, M. M., Samadashwily, G. M., Krasilnikov, A. S. & Mirkin, S. M. Transcription through a simple DNA repeat blocks replication elongation. EMBO J. 17, 5095-5102 (1998).
110. Grabczyk, E., Mancuso, M. & Sammarco, M. C. A persistent RNA. DNA hybrid formed by transcription of the Friedreich ataxia triplet repeat in live bacteria, and by T7 RNAP in vitro. Nucleic Acids Res. 35, 5351-5359 (2007).
111. French, S. Consequences of replication fork movement through transcription units in vivo. Science 258, 1362-1365 (1992).
112. Mirkin, E. V. & Mirkin, S. M. Mechanisms of transcription-replication collisions in bacteria. Mol. Cell Biol. 25, 888-895 (2005).
113. Wellinger, R. E., Prado, F. & Aguilera, A. Replication fork progression is impaired by transcription in hyper-recombinant yeast cells lacking a functional THO complex. Mol. Cell Biol. 26, 3327-3334 (2006).
114. Deshpande, A. M. & Newlon, C. S. DNA replication fork pause sites dependent on transcription. Science 272, 1030-1033 (1996). This paper uses two-dimensional-gel electrophoresis to identify RF pause sites in a transcriptionally active tRNA gene of S. cerevisiae.
115. Azvolinsky, A., Dunaway, S., Torres, J. Z., Bessler, J. B. & Zakian, V. A. The S. cerevisiae Rrm3p DNA helicase moves with the replication fork and affects replication of all yeast chromosomes. Genes Dev. 20, 3104-3116 (2006).
116. McGlynn, P. & Lloyd, R. G. Modulation of RNA polymerase by (p)ppGpp reveals a RecG-dependent mechanism for replication fork progression. Cell 101, 35-45 (2000).
117. Trautinger, B. W., Jaktaji, R. P., Rusakova, E. & Lloyd, R. G. RNA polymerase modulators and DNA repair activities resolve conflicts between DNA replication and transcription. Mol. Cell 19, 247-258 (2005).
118. Brewer, B. J. & Fangman, W. L. A replication fork barrier at the 3′ end of yeast ribosomal RNA genes. Cell 55, 637-643 (1988).
119. Di Noia, J. M. & Neuberger, M. S. Molecular mechanisms of antibody somatic hypermutation. Annu. Rev. Biochem. 76, 1-22 (2007).
120. Daniels, G. A. & Lieber, M. R. RNA:DNA complex formation upon transcription of immunoglobulin switch regions: implications for the mechanism and regulation of class switch recombination. Nucleic Acids Res. 23, 5006-5011 (1995).
121. Reaban, M. E., Lebowitz, J. & Griffin, J. A. Transcription induces the formation of a stable RNA. DNA hybrid in the immunoglobulin alpha switch region. J. Biol. Chem. 269, 21850-21857 (1994).
122. Duquette, M. L., Handa, P., Vincent, J. A., Taylor, A. F. & Maizels, N. Intracellular transcription of G-rich DNAs induces formation of G-loops, novel structures containing G4 DNA. Genes Dev. 18, 1618-1629 (2004).
123. Bransteitter, R., Pham, P., Scharff, M. D. & Goodman, M. F. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc. Natl Acad. Sci. USA 100, 4102-4107 (2003).
124. Chaudhuri, J. et al. Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature 422, 726-730 (2003).
125. -/- mice. J. Exp. Med. 203, 2085-2094 (2006).
126. Nambu, Y. et al. Transcription-coupled events associating with immunoglobulin switch region chromatin. Science 302, 2137-2140 (2003).
127. Besmer, E., Market, E. & Papavasiliou, F. N. The transcription elongation complex directs activation-induced cytidine deaminase-mediated DNA deamination. Mol. Cell Biol. 26, 4378-4385 (2006).
128. Longerich, S. & Storb, U. The contested role of uracil DNA glycosylase in immunoglobulin gene diversification. Trends Genet. 21, 253-256 (2005).
129. Chaudhuri, J., Khuong, C. & Alt, F. W. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430, 992-998 (2004).
130. Casellas, R. et al. Ku80 is required for immunoglobulin isotype switching. EMBO J. 17, 2404-2411 (1998).
131. Manis, J. P. et al. Ku70 is required for late B cell development and immunoglobulin heavy chain class switching. J. Exp. Med. 187, 2081-2089 (1998).
132. Petersen, S. et al. AID is required to initiate Nbs1/ γ-H2AX focus formation and mutations at sites of class switching. Nature 414, 660-665 (2001).
133. Schrader, C. E., Guikema, J. E., Linehan, E. K., Selsing, E. & Stavnezer, J. Activation-induced cytidine deaminase-dependent DNA breaks in class switch recombination occur during G1 phase of the cell cycle and depend upon mismatch repair. J. Immunol. 179, 6064-6071 (2007).
134. Jankovic, M., Nussenzweig, A. & Nussenzweig, M. C. Antigen receptor diversification and chromosome translocations. Nature Immunol. 8, 801-808 (2007).
135. Ramiro, A. R. et al. AID is required for c-Myc/IgH chromosome translocations in vivo. Cell 118, 431-438 (2004). This paper links CSR with chromosomal translocations involving Ig genes and the c-Myc proto-oncogene, and shows that AID is required for these translocations.
136. Duquette, M. L., Huber, M. D. & Maizels, N. G-rich proto-oncogenes are targeted for genomic instability in B-cell lymphomas. Cancer Res. 67, 2586-2594 (2007).
137. Ramiro, A. et al. The role of activation-induced deaminase in antibody diversification and chromosome translocations. Adv. Immunol. 94, 75-107 (2007).
138. Ramiro, A. R. et al. Role of genomic instability and p53 in AID-induced c-Myc-IgH translocations. Nature 440, 105-109 (2006).
139. Yan, C. T. et al. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449, 478-482 (2007).
140. Ward, J. D., Barber, L. J., Petalcorin, M. I., Yanowitz, J. & Boulton, S. J. Replication blocking lesions present a unique substrate for homologous recombination. EMBO J. 26, 3384-3396 (2007).
141. Tercero, J. A. & Diffley, J. F. Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint. Nature 412, 553-557 (2001). This paper describes a primary role for the S-phase checkpoint in preventing irreversible RF collapse. It shows that the checkpoint proteins Mec1 and Rad53 are required for the completion of DNA replication in the presence of the DNA-alkylating agent methyl methanesulphonate.
142. Lopes, M. et al. The DNA replication checkpoint response stabilizes stalled replication forks. Nature 412, 557-561 (2001).
143. Ivessa, A. S., Zhou, J. Q. & Zakian, V. A. The Saccharomyces Pif1p DNA helicase and the highly related Rrm3p have opposite effects on replication fork progression in ribosomal DNA. Cell 100, 479-489 (2000).
144. Katou, Y. et al. S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex. Nature 424, 1078-1083 (2003).
145. Calzada, A., Hodgson, B., Kanemaki, M., Bueno, A. & Labib, K. Molecular anatomy and regulation of a stable replisome at a paused eukaryotic DNA replication fork. Genes Dev. 19, 1905-1919 (2005).
146. Franco, A. A., Lam, W. M., Burgers, P. M. & Kaufman, P. D. Histone deposition protein Asf1 maintains DNA replisome integrity and interacts with replication factor C. Genes Dev. 19, 1365-1375 (2005).
147. Su, T. T. Cellular responses to DNA damage: one signal, multiple choices. Annu. Rev. Genet. 40, 187-208 (2006).
148. Trenz, K., Smith, E., Smith, S. & Costanzo, V. ATM and ATR promote Mre11 dependent restart of collapsed replication forks and prevent accumulation of DNA breaks. EMBO J. 25, 1764-1774 (2006).
149. Liberi, G. et al. Rad51-dependent DNA structures accumulate at damaged replication forks in sgs1 mutants defective in the yeast ortholog of BLM RecQ helicase. Genes Dev. 19, 339-350 (2005).
150. Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S. & Bonner, W. M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858-5868 (1998).
151. Burma, S., Chen, B. P., Murphy, M., Kurimasa, A. & Chen, D. J. ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J. Biol. Chem. 276, 42462-42467 (2001).
152. Strom, L., Lindroos, H. B., Shirahige, K. & Sjogren, C. Postreplicative recruitment of cohesin to double-strand breaks is required for DNA repair. Mol. Cell 16, 1003-1015 (2004).
153. Unal, E. et al. DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain. Mol. Cell 16, 991-1002 (2004).