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Novel insights into molecular chaperone regulation of ribonucleotide reductase

Knighton, Laura E., Delgado, Lena E., Truman, Andrew W.
Current genetics 2019 v.65 no.2 pp. 477-482
adverse effects, alopecia, molecular chaperones, nausea, neoplasm cells, neoplasms, patients, proteome, ribonucleotide reductase, vomiting, yeasts
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.