Proteopedia

5y58

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Crystal structure of Ku70/80 and TLC1Crystal structure of Ku70/80 and TLC1

Structural highlights

5y58 is a 9 chain structure with sequence from [1] and Baker's yeast. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:YKU70, HDF1, NES24, YMR284W, YM8021.10 (Baker's yeast), YKU80, HDF2, YMR106C, YM9718.05C (Baker's yeast)
Activity:DNA helicase, with EC number 3.6.4.12
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[KU70_YEAST] Single-stranded DNA-dependent ATP-dependent helicase. Involved in non-homologous end joining (NHEJ) DNA double strand break repair. DNA-binding is sequence-independent but has a high affinity to nicks in double-stranded DNA and to the ends of duplex DNA. Binds to naturally occurring chromosomal ends, and therefore provides chromosomal end protection. Appears to have a role in recruitment of telomerase and CDC13 to the telomere and the subsequent telomere elongation. Required also for telomere recombination to repair telomeric ends in the absence of telomerase. KU70, of the KU70/KU80 heterodimer, binds to the stem loop of TLC1, the RNA component of telomerase. Involved in telomere maintenance. Interacts with telomeric repeats and subtelomeric sequences thereby controlling telomere length and protecting against subtelomeric rearrangement. Maintains telomeric chromatin, which is involved in silencing the expression of genes located at the telomere. Required for mating-type switching.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [KU80_YEAST] Single-stranded DNA-dependent ATP-dependent helicase. Involved in non-homologous end joining (NHEJ) DNA double strand break repair. DNA-binding is sequence-independent but has a high affinity to nicks in double-stranded DNA and to the ends of duplex DNA. Binds to naturally occurring chromosomal ends, and therefore provides chromosomal end protection. Appears to have a role in recruitment of telomerase and CDC13 to the telomere and the subsequent telomere elongation. Required also for telomere recombination to repair telomeric ends in the absence of telomerase. KU70, of the KU70/KU80 heterodimer, binds to the stem loop of TLC1, the RNA component of telomerase. Involved in telomere maintenance. Interacts with telomeric repeats and subtelomeric sequences thereby controlling telomere length and protecting against subtelomeric rearrangement. Maintains telomeric chromatin, which is involved in silencing the expression of genes located at the telomere. Required for mating-type switching.[12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25]

Publication Abstract from PubMed

Telomerase maintains chromosome ends from humans to yeasts. Recruitment of yeast telomerase to telomeres occurs through its Ku and Est1 subunits via independent interactions with telomerase RNA (TLC1) and telomeric proteins Sir4 and Cdc13, respectively. However, the structures of the molecules comprising these telomerase-recruiting pathways remain unknown. Here, we report crystal structures of the Ku heterodimer and Est1 complexed with their key binding partners. Two major findings are as follows: (1) Ku specifically binds to telomerase RNA in a distinct, yet related, manner to how it binds DNA; and (2) Est1 employs two separate pockets to bind distinct motifs of Cdc13. The N-terminal Cdc13-binding site of Est1 cooperates with the TLC1-Ku-Sir4 pathway for telomerase recruitment, whereas the C-terminal interface is dispensable for binding Est1 in vitro yet is nevertheless essential for telomere maintenance in vivo. Overall, our results integrate previous models and provide fundamentally valuable structural information regarding telomere biology.

Structural Insights into Yeast Telomerase Recruitment to Telomeres.,Chen H, Xue J, Churikov D, Hass EP, Shi S, Lemon LD, Luciano P, Bertuch AA, Zappulla DC, Geli V, Wu J, Lei M Cell. 2018 Jan 11;172(1-2):331-343.e13. doi: 10.1016/j.cell.2017.12.008. Epub, 2017 Dec 28. PMID:29290466[26]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ de la Torre-Ruiz M, Lowndes NF. The Saccharomyces cerevisiae DNA damage checkpoint is required for efficient repair of double strand breaks by non-homologous end joining. FEBS Lett. 2000 Feb 11;467(2-3):311-5. PMID:10675560
  2. ↑ Grandin N, Damon C, Charbonneau M. Cdc13 cooperates with the yeast Ku proteins and Stn1 to regulate telomerase recruitment. Mol Cell Biol. 2000 Nov;20(22):8397-408. PMID:11046137
  3. ↑ Tsai YL, Tseng SF, Chang SH, Lin CC, Teng SC. Involvement of replicative polymerases, Tel1p, Mec1p, Cdc13p, and the Ku complex in telomere-telomere recombination. Mol Cell Biol. 2002 Aug;22(16):5679-87. PMID:12138180
  4. ↑ Stellwagen AE, Haimberger ZW, Veatch JR, Gottschling DE. Ku interacts with telomerase RNA to promote telomere addition at native and broken chromosome ends. Genes Dev. 2003 Oct 1;17(19):2384-95. Epub 2003 Sep 15. PMID:12975323 doi:http://dx.doi.org/10.1101/gad.1125903
  5. ↑ Bertuch AA, Lundblad V. The Ku heterodimer performs separable activities at double-strand breaks and chromosome termini. Mol Cell Biol. 2003 Nov;23(22):8202-15. PMID:14585978
  6. ↑ Mages GJ, Feldmann HM, Winnacker EL. Involvement of the Saccharomyces cerevisiae HDF1 gene in DNA double-strand break repair and recombination. J Biol Chem. 1996 Apr 5;271(14):7910-5. PMID:8626469
  7. ↑ Tsukamoto Y, Kato J, Ikeda H. Hdf1, a yeast Ku-protein homologue, is involved in illegitimate recombination, but not in homologous recombination. Nucleic Acids Res. 1996 Jun 1;24(11):2067-72. PMID:8668537
  8. ↑ Laroche T, Martin SG, Gotta M, Gorham HC, Pryde FE, Louis EJ, Gasser SM. Mutation of yeast Ku genes disrupts the subnuclear organization of telomeres. Curr Biol. 1998 May 21;8(11):653-6. PMID:9635192
  9. ↑ Nugent CI, Bosco G, Ross LO, Evans SK, Salinger AP, Moore JK, Haber JE, Lundblad V. Telomere maintenance is dependent on activities required for end repair of double-strand breaks. Curr Biol. 1998 May 21;8(11):657-60. PMID:9635193
  10. ↑ Polotnianka RM, Li J, Lustig AJ. The yeast Ku heterodimer is essential for protection of the telomere against nucleolytic and recombinational activities. Curr Biol. 1998 Jul 2;8(14):831-4. PMID:9663392
  11. ↑ Evans SK, Sistrunk ML, Nugent CI, Lundblad V. Telomerase, Ku, and telomeric silencing in Saccharomyces cerevisiae. Chromosoma. 1998 Dec;107(6-7):352-8. PMID:9914366
  12. ↑ de la Torre-Ruiz M, Lowndes NF. The Saccharomyces cerevisiae DNA damage checkpoint is required for efficient repair of double strand breaks by non-homologous end joining. FEBS Lett. 2000 Feb 11;467(2-3):311-5. PMID:10675560
  13. ↑ Grandin N, Damon C, Charbonneau M. Cdc13 cooperates with the yeast Ku proteins and Stn1 to regulate telomerase recruitment. Mol Cell Biol. 2000 Nov;20(22):8397-408. PMID:11046137
  14. ↑ Tsai YL, Tseng SF, Chang SH, Lin CC, Teng SC. Involvement of replicative polymerases, Tel1p, Mec1p, Cdc13p, and the Ku complex in telomere-telomere recombination. Mol Cell Biol. 2002 Aug;22(16):5679-87. PMID:12138180
  15. ↑ Stellwagen AE, Haimberger ZW, Veatch JR, Gottschling DE. Ku interacts with telomerase RNA to promote telomere addition at native and broken chromosome ends. Genes Dev. 2003 Oct 1;17(19):2384-95. Epub 2003 Sep 15. PMID:12975323 doi:http://dx.doi.org/10.1101/gad.1125903
  16. ↑ Roy R, Meier B, McAinsh AD, Feldmann HM, Jackson SP. Separation-of-function mutants of yeast Ku80 reveal a Yku80p-Sir4p interaction involved in telomeric silencing. J Biol Chem. 2004 Jan 2;279(1):86-94. Epub 2003 Oct 9. PMID:14551211 doi:http://dx.doi.org/10.1074/jbc.M306841200
  17. ↑ Bertuch AA, Lundblad V. The Ku heterodimer performs separable activities at double-strand breaks and chromosome termini. Mol Cell Biol. 2003 Nov;23(22):8202-15. PMID:14585978
  18. ↑ Ruan C, Workman JL, Simpson RT. The DNA repair protein yKu80 regulates the function of recombination enhancer during yeast mating type switching. Mol Cell Biol. 2005 Oct;25(19):8476-85. doi: 10.1128/MCB.25.19.8476-8485.2005. PMID:16166630 doi:http://dx.doi.org/10.1128/MCB.25.19.8476-8485.2005
  19. ↑ Feldmann H, Driller L, Meier B, Mages G, Kellermann J, Winnacker EL. HDF2, the second subunit of the Ku homologue from Saccharomyces cerevisiae. J Biol Chem. 1996 Nov 1;271(44):27765-9. PMID:8910371
  20. ↑ Boulton SJ, Jackson SP. Identification of a Saccharomyces cerevisiae Ku80 homologue: roles in DNA double strand break rejoining and in telomeric maintenance. Nucleic Acids Res. 1996 Dec 1;24(23):4639-48. PMID:8972848
  21. ↑ Gravel S, Larrivee M, Labrecque P, Wellinger RJ. Yeast Ku as a regulator of chromosomal DNA end structure. Science. 1998 May 1;280(5364):741-4. PMID:9563951
  22. ↑ Laroche T, Martin SG, Gotta M, Gorham HC, Pryde FE, Louis EJ, Gasser SM. Mutation of yeast Ku genes disrupts the subnuclear organization of telomeres. Curr Biol. 1998 May 21;8(11):653-6. PMID:9635192
  23. ↑ Nugent CI, Bosco G, Ross LO, Evans SK, Salinger AP, Moore JK, Haber JE, Lundblad V. Telomere maintenance is dependent on activities required for end repair of double-strand breaks. Curr Biol. 1998 May 21;8(11):657-60. PMID:9635193
  24. ↑ Polotnianka RM, Li J, Lustig AJ. The yeast Ku heterodimer is essential for protection of the telomere against nucleolytic and recombinational activities. Curr Biol. 1998 Jul 2;8(14):831-4. PMID:9663392
  25. ↑ Evans SK, Sistrunk ML, Nugent CI, Lundblad V. Telomerase, Ku, and telomeric silencing in Saccharomyces cerevisiae. Chromosoma. 1998 Dec;107(6-7):352-8. PMID:9914366
  26. ↑ Chen H, Xue J, Churikov D, Hass EP, Shi S, Lemon LD, Luciano P, Bertuch AA, Zappulla DC, Geli V, Wu J, Lei M. Structural Insights into Yeast Telomerase Recruitment to Telomeres. Cell. 2018 Jan 11;172(1-2):331-343.e13. doi: 10.1016/j.cell.2017.12.008. Epub, 2017 Dec 28. PMID:29290466 doi:http://dx.doi.org/10.1016/j.cell.2017.12.008

5y58, resolution 2.80Å

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