Inhibition of Telomere Recombination by Inactivation of KEOPS Subunit Cgi121 Promotes Cell Longevity

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Aging is a general biological process among the living organisms which is affected by environmental stimuli but also genetically controlled. Genome instability is one of the aging hallmarks and has long been implicated as one of the main causal factors in aging. DNA double strand breaks (DSBs) are the most deleterious DNA damages that cause genome instability. To counteract DNA damage of DSBs and maintain high level of genome integrity, cells have evolved powerful repair systems such as homologous recombination (HR). HR is crucial for DNA repair and genome integrity maintenance, and is generally believed to be essential for assurance of cell longevity. Telomeres, the physical ends of eukaryotic linear chromosomes, are preferentially elongated by telomerase, a specialized reverse transcriptase, in most cases. However, due to the resemblance of telomeres to DSBs, HR can not be eliminated but rather readily takes place on telomeres, even in the presence of telomerase. Here we show that HR at yeast telomeres elicits genome instability and accelerates cellular aging. Inactivation of the evolutionarily conserved KEOPS complex subunit Cgi121 specifically inhibits telomere HR and results in extremely long lifespan, indicating a dark side of HR in longevity regulation.

Vyšlo v časopise: Inhibition of Telomere Recombination by Inactivation of KEOPS Subunit Cgi121 Promotes Cell Longevity. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1005071
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005071

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Zdroje

1. Guarente L, Kenyon C (2000) Genetic pathways that regulate ageing in model organisms. Nature 408 : 255–262. 11089983

2. Longo VD, Shadel GS, Kaeberlein M, Kennedy B (2012) Replicative and chronological aging in Saccharomyces cerevisiae. Cell Metab 16 : 18–31. doi: 10.1016/j.cmet.2012.06.002 22768836

3. Kaeberlein M (2010) Lessons on longevity from budding yeast. Nature 464 : 513–519. doi: 10.1038/nature08981 20336133

4. Barton AA (1950) Some aspects of cell division in saccharomyces cerevisiae. J Gen Microbiol 4 : 84–86. 15415559

5. Mortimer RK, Johnston JR (1959) Life span of individual yeast cells. Nature 183 : 1751–1752. 13666896

6. Hoeijmakers JH (2009) DNA damage, aging, and cancer. N Engl J Med 361 : 1475–1485. doi: 10.1056/NEJMra0804615 19812404

7. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153 : 1194–1217. doi: 10.1016/j.cell.2013.05.039 23746838

8. McMurray MA, Gottschling DE (2004) Aging and genetic instability in yeast. Curr Opin Microbiol 7 : 673–679. 15556042

9. Burtner CR, Kennedy BK (2010) Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol 11 : 567–578. doi: 10.1038/nrm2944 20651707

10. Sinclair DA, Guarente L (1997) Extrachromosomal rDNA circles—a cause of aging in yeast. Cell 91 : 1033–1042. 9428525

11. Park PU, Defossez PA, Guarente L (1999) Effects of mutations in DNA repair genes on formation of ribosomal DNA circles and life span in Saccharomyces cerevisiae. Mol Cell Biol 19 : 3848–3856. 10207108

12. McEachern MJ, Krauskopf A, Blackburn EH (2000) Telomeres and their control. Annu Rev Genet 34 : 331–358. 11092831

13. Wellinger RJ, Wolf AJ, Zakian VA (1993) Saccharomyces telomeres acquire single-strand TG1–3 tails late in S phase. Cell 72 : 51–60. 8422682

14. Wellinger RJ, Zakian VA (2012) Everything you ever wanted to know about Saccharomyces cerevisiae telomeres: beginning to end. Genetics 191 : 1073–1105. doi: 10.1534/genetics.111.137851 22879408

15. Lingner J, Cech TR, Hughes TR, Lundblad V (1997) Three Ever Shorter Telomere (EST) genes are dispensable for in vitro yeast telomerase activity. Proc Natl Acad Sci U S A 94 : 11190–11195. 9326584

16. Singer MS, Gottschling DE (1994) TLC1: template RNA component of Saccharomyces cerevisiae telomerase. Science 266 : 404–409. 7545955

17. Greider CW, Blackburn EH (1985) Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43 : 405–413. 3907856

18. Tong XJ, Li QJ, Duan YM, Liu NN, Zhang ML, et al. (2011) Est1 protects telomeres and inhibits subtelomeric y'-element recombination. Mol Cell Biol 31 : 1263–1274. doi: 10.1128/MCB.00831-10 21220516

19. Lundblad V, Szostak JW (1989) A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57 : 633–643. 2655926

20. Lendvay TS, Morris DK, Sah J, Balasubramanian B, Lundblad V (1996) Senescence mutants of Saccharomyces cerevisiae with a defect in telomere replication identify three additional EST genes. Genetics 144 : 1399–1412. 8978029

21. Boulton SJ, Jackson SP (1996) Identification of a Saccharomyces cerevisiae Ku80 homologue: roles in DNA double strand break rejoining and in telomeric maintenance. Nucleic Acids Res 24 : 4639–4648. 8972848

22. Milne GT, Jin S, Shannon KB, Weaver DT (1996) Mutations in two Ku homologs define a DNA end-joining repair pathway in Saccharomyces cerevisiae. Mol Cell Biol 16 : 4189–4198. 8754818

23. Polotnianka RM, Li J, Lustig AJ (1998) The yeast Ku heterodimer is essential for protection of the telomere against nucleolytic and recombinational activities. Curr Biol 8 : 831–834. 9663392

24. Boulton SJ, Jackson SP (1998) Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing. EMBO J 17 : 1819–1828. 9501103

25. Gravel S, Larrivee M, Labrecque P, Wellinger RJ (1998) Yeast Ku as a regulator of chromosomal DNA end structure. Science 280 : 741–744. 9563951

26. Fisher TS, Taggart AK, Zakian VA (2004) Cell cycle-dependent regulation of yeast telomerase by Ku. Nat Struct Mol Biol 11 : 1198–1205. 15531893

27. Stellwagen AE, Haimberger ZW, Veatch JR, Gottschling DE (2003) Ku interacts with telomerase RNA to promote telomere addition at native and broken chromosome ends. Genes Dev 17 : 2384–2395. 12975323

28. DuBois ML, Haimberger ZW, McIntosh MW, Gottschling DE (2002) A quantitative assay for telomere protection in Saccharomyces cerevisiae. Genetics 161 : 995–1013. 12136006

29. Nakada D, Hirano Y, Sugimoto K (2004) Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway. Mol Cell Biol 24 : 10016–10025. 15509802

30. Mimitou EP, Symington LS (2008) Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455 : 770–774. doi: 10.1038/nature07312 18806779

31. Nakada D, Matsumoto K, Sugimoto K (2003) ATM-related Tel1 associates with double-strand breaks through an Xrs2-dependent mechanism. Genes Dev 17 : 1957–1962. 12923051

32. McEachern MJ, Haber JE (2006) Break-induced replication and recombinational telomere elongation in yeast. Annu Rev Biochem 75 : 111–135. 16756487

33. Downey M, Houlsworth R, Maringele L, Rollie A, Brehme M, et al. (2006) A genome-wide screen identifies the evolutionarily conserved KEOPS complex as a telomere regulator. Cell 124 : 1155–1168. 16564010

34. Kisseleva-Romanova E, Lopreiato R, Baudin-Baillieu A, Rousselle JC, Ilan L, et al. (2006) Yeast homolog of a cancer-testis antigen defines a new transcription complex. EMBO J 25 : 3576–3585. 16874308

35. Hu Y, Tang HB, Liu NN, Tong XJ, Dang W, et al. (2013) Telomerase-null survivor screening identifies novel telomere recombination regulators. PLoS Genet 9: e1003208. doi: 10.1371/journal.pgen.1003208 23390378

36. El Yacoubi B, Hatin I, Deutsch C, Kahveci T, Rousset JP, et al. (2011) A role for the universal Kae1/Qri7/YgjD (COG0533) family in tRNA modification. EMBO J 30 : 882–893. doi: 10.1038/emboj.2010.363 21285948

37. Srinivasan M, Mehta P, Yu Y, Prugar E, Koonin EV, et al. (2011) The highly conserved KEOPS/EKC complex is essential for a universal tRNA modification, t6A. EMBO J 30 : 873–881. doi: 10.1038/emboj.2010.343 21183954

38. Lundblad V, Blackburn EH (1993) An alternative pathway for yeast telomere maintenance rescues est1 -⁠ senescence. Cell 73 : 347–360. 8477448

39. Teng SC, Zakian VA (1999) Telomere-telomere recombination is an efficient bypass pathway for telomere maintenance in Saccharomyces cerevisiae. Mol Cell Biol 19 : 8083–8093. 10567534

40. Chen XF, Meng FL, Zhou JQ (2009) Telomere recombination accelerates cellular aging in Saccharomyces cerevisiae. PLoS Genet 5: e1000535. doi: 10.1371/journal.pgen.1000535 19557187

41. Liti G, Louis EJ (2003) NEJ1 prevents NHEJ-dependent telomere fusions in yeast without telomerase. Mol Cell 11 : 1373–1378. 12769859

42. Li B, Lustig AJ (1996) A novel mechanism for telomere size control in Saccharomyces cerevisiae. Genes Dev 10 : 1310–1326. 8647430

43. Wang RC, Smogorzewska A, de Lange T (2004) Homologous recombination generates T-loop-sized deletions at human telomeres. Cell 119 : 355–368. 15507207

44. Bechter OE, Zou Y, Shay JW, Wright WE (2003) Homologous recombination in human telomerase-positive and ALT cells occurs with the same frequency. EMBO Rep 4 : 1138–1143. 14618159

45. Diede SJ, Gottschling DE (1999) Telomerase-mediated telomere addition in vivo requires DNA primase and DNA polymerases alpha and delta. Cell 99 : 723–733. 10619426

46. Signon L, Malkova A, Naylor ML, Klein H, Haber JE (2001) Genetic requirements for RAD51 -⁠ and RAD54-independent break-induced replication repair of a chromosomal double-strand break. Mol Cell Biol 21 : 2048–2056. 11238940

47. Le S, Moore JK, Haber JE, Greider CW (1999) RAD50 and RAD51 define two pathways that collaborate to maintain telomeres in the absence of telomerase. Genetics 152 : 143–152. 10224249

48. Malkova A, Ivanov EL, Haber JE (1996) Double-strand break repair in the absence of RAD51 in yeast: a possible role for break-induced DNA replication. Proc Natl Acad Sci U S A 93 : 7131–7136. 8692957

49. Mao DY, Neculai D, Downey M, Orlicky S, Haffani YZ, et al. (2008) Atomic structure of the KEOPS complex: an ancient protein kinase-containing molecular machine. Mol Cell 32 : 259–275. doi: 10.1016/j.molcel.2008.10.002 18951093

50. Hecker A, Lopreiato R, Graille M, Collinet B, Forterre P, et al. (2008) Structure of the archaeal Kae1/Bud32 fusion protein MJ1130: a model for the eukaryotic EKC/KEOPS subcomplex. EMBO J 27 : 2340–2351. doi: 10.1038/emboj.2008.157 19172740

51. Forstemann K, Hoss M, Lingner J (2000) Telomerase-dependent repeat divergence at the 3' ends of yeast telomeres. Nucleic Acids Res 28 : 2690–2694. 10908324

52. Meng FL, Hu Y, Shen N, Tong XJ, Wang J, et al. (2009) Sua5p a single-stranded telomeric DNA-binding protein facilitates telomere replication. EMBO J 28 : 1466–1478. doi: 10.1038/emboj.2009.92 19369944

53. Evans SK, Lundblad V (1999) Est1 and Cdc13 as comediators of telomerase access. Science 286 : 117–120. 10506558

54. Kaeberlein M, McVey M, Guarente L (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13 : 2570–2580. 10521401

55. Bertuch AA, Lundblad V (2003) The Ku heterodimer performs separable activities at double-strand breaks and chromosome termini. Mol Cell Biol 23 : 8202–8215. 14585978

56. Petes TD, Botstein D (1977) Simple Mendelian inheritance of the reiterated ribosomal DNA of yeast. Proc Natl Acad Sci U S A 74 : 5091–5095. 337310

57. Philippsen P, Thomas M, Kramer RA, Davis RW (1978) Unique arrangement of coding sequences for 5 S, 5.8 S, 18 S and 25 S ribosomal RNA in Saccharomyces cerevisiae as determined by R-loop and hybridization analysis. J Mol Biol 123 : 387–404. 357737

58. Rustchenko EP, Sherman F (1994) Physical constitution of ribosomal genes in common strains of Saccharomyces cerevisiae. Yeast 10 : 1157–1171. 7754705

59. Kobayashi T, Horiuchi T (1996) A yeast gene product, Fob1 protein, required for both replication fork blocking and recombinational hotspot activities. Genes Cells 1 : 465–474. 9078378

60. Johzuka K, Horiuchi T (2002) Replication fork block protein, Fob1, acts as an rDNA region specific recombinator in S. cerevisiae. Genes Cells 7 : 99–113. 11895475

61. Kobayashi T, Heck DJ, Nomura M, Horiuchi T (1998) Expansion and contraction of ribosomal DNA repeats in Saccharomyces cerevisiae: requirement of replication fork blocking (Fob1) protein and the role of RNA polymerase I. Genes Dev 12 : 3821–3830. 9869636

62. Defossez PA, Prusty R, Kaeberlein M, Lin SJ, Ferrigno P, et al. (1999) Elimination of replication block protein Fob1 extends the life span of yeast mother cells. Mol Cell 3 : 447–455. 10230397

63. Bryk M, Banerjee M, Murphy M, Knudsen KE, Garfinkel DJ, et al. (1997) Transcriptional silencing of Ty1 elements in the RDN1 locus of yeast. Genes Dev 11 : 255–269. 9009207

64. Smith JS, Boeke JD (1997) An unusual form of transcriptional silencing in yeast ribosomal DNA. Genes Dev 11 : 241–254. 9009206

65. Gottlieb S, Esposito RE (1989) A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA. Cell 56 : 771–776. 2647300

66. Anderson RM, Weindruch R (2012) The caloric restriction paradigm: implications for healthy human aging. Am J Hum Biol 24 : 101–106. doi: 10.1002/ajhb.22243 22290875

67. Katewa SD, Kapahi P (2010) Dietary restriction and aging, 2009. Aging Cell 9 : 105–112. doi: 10.1111/j.1474-9726.2010.00552.x 20096035

68. Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD (2001) Regulation of longevity and stress resistance by Sch9 in yeast. Science 292 : 288–290. 11292860

69. Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, et al. (2005) Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310 : 1193–1196. 16293764

70. Lin SJ, Defossez PA, Guarente L (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289 : 2126–2128. 11000115

71. Powers RW 3rd, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S (2006) Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 20 : 174–184. 16418483

72. Kaeberlein M, Kirkland KT, Fields S, Kennedy BK (2005) Genes determining yeast replicative life span in a long-lived genetic background. Mech Ageing Dev 126 : 491–504. 15722108

73. Kaeberlein M, Steffen KK, Hu D, Dang N, Kerr EO, et al. (2006) Comment on "HST2 mediates SIR2-independent life-span extension by calorie restriction". Science 312 : 1312; author reply 1312. 16741098

74. Gebre S, Connor R, Xia Y, Jawed S, Bush JM, et al. (2012) Osh6 overexpression extends the lifespan of yeast by increasing vacuole fusion. Cell Cycle 11 : 2176–2188. doi: 10.4161/cc.20691 22622083

75. de Lange T (2004) T-loops and the origin of telomeres. Nat Rev Mol Cell Biol 5 : 323–329. 15071557

76. Iyer S, Chadha AD, McEachern MJ (2005) A mutation in the STN1 gene triggers an alternative lengthening of telomere-like runaway recombinational telomere elongation and rapid deletion in yeast. Mol Cell Biol 25 : 8064–8073. 16135798

77. Sikorski RS, Hieter P (1989) A system of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics 122 : 19–27. 2659436