Novel insights into molecular chaperone regulation of ribonucleotide reductase
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.
KeywordsRibonucleotide reductase Molecular chaperones Hsp70 Hsp90 Ydj1 Hdj2 DNA damage response
This work was supported by NCI R15CA208773 (AWT) and NSF REU 1359271 (LED). We would like to thank Nitika for critical reading.
- 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
- 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
- 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
- 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
- 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
- Yarbro JW (1992) Mechanism of action of hydroxyurea. Semin Oncol 19:1–10Google Scholar