Advertisement

Novel insights into molecular chaperone regulation of ribonucleotide reductase

  • Laura E. Knighton
  • Lena E. Delgado
  • Andrew W. Truman
Mini-Review

Abstract

The molecular chaperones Hsp70 and Hsp90 bind and fold a significant proportion of the proteome. They are responsible for the activity and stability of many disease-related proteins including those in cancer. Substantial effort has been devoted to developing a range of chaperone inhibitors for clinical use. Recent studies have identified the oncogenic ribonucleotide reductase (RNR) complex as an interactor of chaperones. While several generations of RNR inhibitor have been developed for use in cancer patients, many of these produce severe side effects such as nausea, vomiting and hair loss. Development of more potent, less patient-toxic anti-RNR strategies would be highly desirable. Inhibition of chaperones and associated co-chaperone molecules in both cancer and model organisms such as budding yeast result in the destabilization of RNR subunits and a corresponding sensitization to RNR inhibitors. Going forward, this may form part of a novel strategy to target cancer cells that are resistant to standard RNR inhibitors.

Keywords

Ribonucleotide reductase Molecular chaperones Hsp70 Hsp90 Ydj1 Hdj2 DNA damage response 

Notes

Acknowledgements

This work was supported by NCI R15CA208773 (AWT) and NSF REU 1359271 (LED). We would like to thank Nitika for critical reading.

References

  1. Amin-Wetzel N, Saunders RA, Kamphuis MJ, Rato C, Preissler S, Harding HP, Ron D (2017) A J-protein co-chaperone recruits BiP to monomerize IRE1 and repress the unfolded protein response. Cell 171:1625–1637.  https://doi.org/10.1016/j.cell.2017.10.040 (e1613) CrossRefGoogle Scholar
  2. Arlander SJ, Eapen AK, Vroman BT, McDonald RJ, Toft DO, Karnitz LM (2003) Hsp90 inhibition depletes Chk1 and sensitizes tumor cells to replication stress. J Biol Chem 278:52572–52577.  https://doi.org/10.1074/jbc.M309054200 CrossRefGoogle Scholar
  3. Aron R, Higurashi T, Sahi C, Craig EA (2007) J-protein co-chaperone Sis1 required for generation of [RNQ+] seeds necessary for prion propagation. EMBO J 26:3794–3803.  https://doi.org/10.1038/sj.emboj.7601811 CrossRefGoogle Scholar
  4. Assimon VA, Gillies AT, Rauch JN, Gestwicki JE (2013) Hsp70 protein complexes as drug targets. Curr Pharm Des 19:404–417CrossRefGoogle Scholar
  5. Bachman AB et al (2018) Phosphorylation induced cochaperone unfolding promotes kinase recruitment and client class-specific Hsp90 phosphorylation. Nat Commun 9:265.  https://doi.org/10.1038/s41467-017-02711-w CrossRefGoogle Scholar
  6. Calderwood SK (2013) Molecular cochaperones: tumor growth and cancer treatment. Scientifica (Cairo) 2013:217513  https://doi.org/10.1155/2013/217513 CrossRefGoogle Scholar
  7. Calderwood SK, Gong J (2016) Heat shock proteins promote cancer: it’s a protection racket. Trends Biochem Sci 41:311–323.  https://doi.org/10.1016/j.tibs.2016.01.003 CrossRefGoogle Scholar
  8. Calderwood SK, Neckers L (2016) Hsp90 in cancer: transcriptional roles in the nucleus. Adv Cancer Res 129:89–106.  https://doi.org/10.1016/bs.acr.2015.08.002 CrossRefGoogle Scholar
  9. Caplan AJ (2003) What is a co-chaperone? Cell Stress Chaperones 8:105–107CrossRefGoogle Scholar
  10. Cerqueira NM, Pereira S, Fernandes PA, Ramos MJ (2005) Overview of ribonucleotide reductase inhibitors: an appealing target in anti-tumour therapy. Curr Med Chem 12:1283–1294CrossRefGoogle Scholar
  11. Cerqueira NM, Fernandes PA, Ramos MJ (2007a) Ribonucleotide reductase: a critical enzyme for cancer chemotherapy and antiviral agents Recent. Pat Anticancer Drug Discov 2:11–29CrossRefGoogle Scholar
  12. Cerqueira NM, Fernandes PA, Ramos MJ (2007b) Understanding ribonucleotide reductase inactivation by gemcitabine. Chemistry 13:8507–8515  https://doi.org/10.1002/chem.200700260 CrossRefGoogle Scholar
  13. Cesa LC et al (2018) X-linked inhibitor of apoptosis protein (XIAP) is a client of heat shock protein 70 (Hsp70) and a biomarker of its inhibition. J Biol Chem 293:2370–2380.  https://doi.org/10.1074/jbc.RA117.000634 CrossRefGoogle Scholar
  14. Chabes A, Domkin V, Larsson G, Liu A, Graslund A, Wijmenga S, Thelander L (2000) Yeast ribonucleotide reductase has a heterodimeric iron-radical-containing subunit. Proc Natl Acad Sci USA 97:2474–2479CrossRefGoogle Scholar
  15. Connell P, Ballinger CA, Jiang J, Wu Y, Thompson LJ, Hohfeld J, Patterson C (2001) The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol 3:93–96.  https://doi.org/10.1038/35050618 CrossRefGoogle Scholar
  16. Craig EA, Marszalek J (2017) How do J-proteins get Hsp70 to do so many different things? Trends Biochem Sci 42:355–368.  https://doi.org/10.1016/j.tibs.2017.02.007 CrossRefGoogle Scholar
  17. Dong J, Wu Z, Wang D, Pascal LE, Nelson JB, Wipf P, Wang Z (2018) Hsp70 binds to the androgen receptor N-terminal domain and modulates the receptor function in prostate cancer cells. Mol Cancer Ther.  https://doi.org/10.1158/1535-7163.MCT-18-0432 CrossRefGoogle Scholar
  18. Dunn DM et al (2015) c-Abl mediated tyrosine phosphorylation of Aha1 activates its co-chaperone function in cancer. Cells Cell Rep 12:1006–1018.  https://doi.org/10.1016/j.celrep.2015.07.004 CrossRefGoogle Scholar
  19. Erlichman C (2009) Tanespimycin: the opportunities and challenges of targeting heat shock protein 90. Expert Opin Investig Drugs 18:861–868.  https://doi.org/10.1517/13543780902953699 CrossRefGoogle Scholar
  20. Fan CY, Lee S, Cyr DM (2003) Mechanisms for regulation of Hsp70 function by Hsp40. Cell Stress Chaperones 8:309–316CrossRefGoogle Scholar
  21. Freilich R, Arhar T, Abrams JL, Gestwicki JE (2018) Protein-protein interactions in the molecular chaperone network. Acc Chem Res 51:940–949.  https://doi.org/10.1021/acs.accounts.8b00036 CrossRefGoogle Scholar
  22. Galluzzi L, Giordanetto F, Kroemer G (2009) Targeting HSP70 for cancer therapy. Mol Cell 36:176–177.  https://doi.org/10.1016/j.molcel.2009.10.003 CrossRefGoogle Scholar
  23. Ghadban T et al (2017) HSP90 is a promising target in gemcitabine and 5-fluorouracil resistant pancreatic cancer. Apoptosis 22:369–380.  https://doi.org/10.1007/s10495-016-1332-4 CrossRefGoogle Scholar
  24. Gopinath RK, Leu JY (2017) Hsp90 mediates the crosstalk between galactose metabolism and cell morphology pathways in yeast. Curr Genet 63:23–27.  https://doi.org/10.1007/s00294-016-0614-2 CrossRefGoogle Scholar
  25. Hallett ST et al (2017) Differential regulation of G1 CDK complexes by the Hsp90-Cdc37 chaperone system. Cell Rep 21:1386–1398.  https://doi.org/10.1016/j.celrep.2017.10.042 CrossRefGoogle Scholar
  26. He HL et al (2015) Overexpression of DNAJC12 predicts poor response to neoadjuvant concurrent chemoradiotherapy in patients with rectal cancer. Exp Mol Pathol 98:338–345.  https://doi.org/10.1016/j.yexmp.2015.03.029 CrossRefGoogle Scholar
  27. Hubscher V, Mudholkar K, Rospert S (2017) The yeast Hsp70 homolog Ssb: a chaperone for general de novo protein folding and a nanny for specific intrinsically disordered protein domains. Curr Genet 63:9–13.  https://doi.org/10.1007/s00294-016-0610-6 CrossRefGoogle Scholar
  28. Joshi S, Wang T, Araujo TLS, Sharma S, Brodsky JL, Chiosis G (2018) Adapting to stress—chaperome networks in cancer. Nat Rev Cancer 18:562–575.  https://doi.org/10.1038/s41568-018-0020-9 CrossRefGoogle Scholar
  29. Kampinga HH, Craig EA (2011) The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol 11:579–592.  https://doi.org/10.1038/nrm2941 CrossRefGoogle Scholar
  30. Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU (2013) Molecular chaperone functions in protein folding and proteostasis. Ann Rev Biochem 82:323–355.  https://doi.org/10.1146/annurev-biochem-060208-092442 CrossRefGoogle Scholar
  31. Li QQ et al (2017) Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics. Sci Rep 7:201.  https://doi.org/10.1038/s41598-017-00143-6 CrossRefGoogle Scholar
  32. Lianos GD et al (2015) The role of heat shock proteins in cancer. Cancer Lett 360:114–118.  https://doi.org/10.1016/j.canlet.2015.02.026 CrossRefGoogle Scholar
  33. Lu Z, Cyr DM (1998) Protein folding activity of Hsp70 is modified differentially by the hsp40 co-chaperones Sis1 and Ydj1. J Biol Chem 273:27824–27830CrossRefGoogle Scholar
  34. Maicher A, Kupiec M (2018) Rnr1’s role in telomere elongation cannot be replaced by Rnr3: a role beyond dNTPs? Curr Genet 64:547–550.  https://doi.org/10.1007/s00294-017-0779-3 CrossRefGoogle Scholar
  35. McClellan AJ, Xia Y, Deutschbauer AM, Davis RW, Gerstein M, Frydman J (2007) Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approaches. Cell 131:121–135.  https://doi.org/10.1016/j.cell.2007.07.036 CrossRefGoogle Scholar
  36. Mikolaskova B, Jurcik M, Cipakova I, Kretova M, Chovanec M, Cipak L (2018) Maintenance of genome stability: the unifying role of interconnections between the DNA damage response and RNA-processing pathways. Curr Genet 64:971–983.  https://doi.org/10.1007/s00294-018-0819-7 CrossRefGoogle Scholar
  37. Mollapour M, Neckers L (2011) Detecting HSP90 phosphorylation. Methods Mol Biol 787:67–74.  https://doi.org/10.1007/978-1-61779-295-3_5 CrossRefGoogle Scholar
  38. Mollapour M, Tsutsumi S, Neckers L (2010) Hsp90 phosphorylation, Wee1 and the cell cycle. Cell Cycle 9:2310–2316CrossRefGoogle Scholar
  39. Mollapour M et al (2011) Threonine 22 phosphorylation attenuates Hsp90 interaction with cochaperones and affects its chaperone activity. Mol Cell 41:672–681.  https://doi.org/10.1016/j.molcel.2011.02.011 CrossRefGoogle Scholar
  40. Moses MA et al (2018) Targeting the Hsp40/Hsp70 chaperone axis as a novel strategy to treat castration-resistant prostate. Cancer Cancer Res 78:4022–4035.  https://doi.org/10.1158/0008-5472.CAN-17-3728 CrossRefGoogle Scholar
  41. Mulder KW, Winkler GS, Timmers HT (2005) DNA damage and replication stress induced transcription of RNR genes is dependent on the Ccr4-Not complex. Nucleic Acids Res 33:6384–6392.  https://doi.org/10.1093/nar/gki938 CrossRefGoogle Scholar
  42. Muller P, Ruckova E, Halada P, Coates PJ, Hrstka R, Lane DP, Vojtesek B (2013) C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances. Oncogene 32:3101–3110.  https://doi.org/10.1038/onc.2012.314 CrossRefGoogle Scholar
  43. Nitika, Truman AW (2017) Cracking the chaperone code: cellular roles for Hsp70 phosphorylation. Trends Biochem Sci 42:932–935.  https://doi.org/10.1016/j.tibs.2017.10.002 CrossRefGoogle Scholar
  44. Nordlund P, Reichard P (2006) Ribonucleotide reductases. Ann Rev Biochem 75:681–706.  https://doi.org/10.1146/annurev.biochem.75.103004.142443 CrossRefGoogle Scholar
  45. Parrales A, Ranjan A, Iyer SV, Padhye S, Weir SJ, Roy A, Iwakuma T (2016) DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway. Nat Cell Biol 18:1233–1243.  https://doi.org/10.1038/ncb3427 CrossRefGoogle Scholar
  46. Pedersen KS, Kim GP, Foster NR, Wang-Gillam A, Erlichman C, McWilliams RR (2015) Phase II trial of gemcitabine and tanespimycin (17AAG) in metastatic pancreatic cancer: a Mayo Clinic Phase II Consortium study. Invest New Drugs 33:963–968.  https://doi.org/10.1007/s10637-015-0246-2 CrossRefGoogle Scholar
  47. Pennisi R, Ascenzi P, di Masi A (2015) Hsp90: a new player in DNA repair? Biomolecules 5:2589–2618.  https://doi.org/10.3390/biom5042589 CrossRefGoogle Scholar
  48. Perlstein DL, Ge J, Ortigosa AD, Robblee JH, Zhang Z, Huang M, Stubbe J (2005) The active form of the Saccharomyces cerevisiae ribonucleotide reductase small subunit is a heterodimer in vitro and in vivo. Biochemistry 44:15366–15377  https://doi.org/10.1021/bi051616&%23x002B; CrossRefGoogle Scholar
  49. Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R, Gandhi V (1995) Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol 22:3–10Google Scholar
  50. Rodina A et al (2016) The epichaperome is an integrated chaperome network that facilitates tumour survival. Nature 538:397–401.  https://doi.org/10.1038/nature19807 CrossRefGoogle Scholar
  51. Sato N, Torigoe T (1998) The molecular chaperones in cell cycle control. Ann N Y Acad Sci 851:61–66CrossRefGoogle Scholar
  52. Sherman MY, Gabai VL (2015) Hsp70 in cancer: back to the future. Oncogene 34:4153–4161.  https://doi.org/10.1038/onc.2014.349 CrossRefGoogle Scholar
  53. Singh A, Xu YJ (2016) The cell killing mechanisms of hydroxyurea. Genes (Basel).  https://doi.org/10.3390/genes7110099 CrossRefGoogle Scholar
  54. Sluder IT, Nitika, Knighton LE, Truman AW (2018) The Hsp70 co-chaperone Ydj1/HDJ2 regulates ribonucleotide reductase activity. PLoS Genet 14:e1007462.  https://doi.org/10.1371/journal.pgen.1007462 CrossRefGoogle Scholar
  55. Sopha P, Ren HY, Grove DE, Cyr DM (2017) Endoplasmic reticulum stress-induced degradation of DNAJB12 stimulates BOK accumulation and primes cancer cells for apoptosis. J Biol Chem 292:11792–11803.  https://doi.org/10.1074/jbc.M117.785113 CrossRefGoogle Scholar
  56. Tai W, Guzman ML, Chiosis G (2016) The epichaperome: the power of many as the power of one. Oncoscience 3:266–267.  https://doi.org/10.18632/oncoscience.321 CrossRefGoogle Scholar
  57. Taipale M, Krykbaeva I, Koeva M, Kayatekin C, Westover KD, Karras GI, Lindquist S (2012) Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 150:987–1001.  https://doi.org/10.1016/j.cell.2012.06.047 CrossRefGoogle Scholar
  58. Taldone T, Ochiana SO, Patel PD, Chiosis G (2014) Selective targeting of the stress chaperome as a therapeutic strategy. Trends Pharmacol Sci 35:592–603.  https://doi.org/10.1016/j.tips.2014.09.001 CrossRefGoogle Scholar
  59. Tracz-Gaszewska Z et al (2017) Molecular chaperones in the acquisition of cancer cell chemoresistance with mutated TP53 and MDM2 up-regulation. Oncotarget 8:82123–82143  https://doi.org/10.18632/oncotarget.18899 CrossRefGoogle Scholar
  60. Trepel J, Mollapour M, Giaccone G, Neckers L (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10:537–549.  https://doi.org/10.1038/nrc2887 CrossRefGoogle Scholar
  61. Truman AW et al (2006) Expressed in the yeast Saccharomyces cerevisiae, human ERK5 is a client of the Hsp90 chaperone that complements loss of the Slt2p (Mpk1p) cell integrity stress-activated protein kinase. Eukaryot Cell 5:1914–1924.  https://doi.org/10.1128/EC.00263-06 CrossRefGoogle Scholar
  62. Truman AW et al (2012) CDK-dependent Hsp70 Phosphorylation controls G1 cyclin abundance and cell-cycle progression. Cell 151:1308–1318.  https://doi.org/10.1016/j.cell.2012.10.051 CrossRefGoogle Scholar
  63. Truman AW et al (2015a) The quantitative changes in the yeast Hsp70 and Hsp90 interactomes upon DNA damage. Data Brief 2:12–15.  https://doi.org/10.1016/j.dib.2014.10.006 CrossRefGoogle Scholar
  64. Truman AW et al (2015b) Quantitative proteomics of the yeast Hsp70/Hsp90 interactomes during DNA damage reveal chaperone-dependent regulation of ribonucleotide reductase. J Proteom 112:285–300.  https://doi.org/10.1016/j.jprot.2014.09.028 CrossRefGoogle Scholar
  65. Vaughan CK et al (2008) Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc 37. Mol Cell 31:886–895.  https://doi.org/10.1016/j.molcel.2008.07.021 CrossRefGoogle Scholar
  66. Wang PJ, Chabes A, Casagrande R, Tian XC, Thelander L, Huffaker TC (1997) Rnr4p, a novel ribonucleotide reductase small-subunit protein. Mol Cell Biol 17:6114–6121CrossRefGoogle Scholar
  67. Weeks SA, Miller DJ (2008) The heat shock protein 70 cochaperone YDJ1 is required for efficient membrane-specific flock house virus RNA replication complex assembly and function in Saccharomyces cerevisiae. J Virol 82:2004–2012.  https://doi.org/10.1128/JVI.02017-07 CrossRefGoogle Scholar
  68. Wegele H, Muller L, Buchner J (2004) Hsp70 and Hsp90—a relay team for protein folding. Rev Physiol Biochem Pharmacol 151:1–44.  https://doi.org/10.1007/s10254-003-0021-1 CrossRefGoogle Scholar
  69. Woodford MR et al (2016) Mps1 mediated phosphorylation of Hsp90 confers renal cell carcinoma sensitivity and selectivity to Hsp90. Inhibitors Cell Rep 14:872–884.  https://doi.org/10.1016/j.celrep.2015.12.084 CrossRefGoogle Scholar
  70. Yarbro JW (1992) Mechanism of action of hydroxyurea. Semin Oncol 19:1–10Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biological SciencesThe University of North Carolina at CharlotteCharlotteUSA

Personalised recommendations