Novel insights into molecular chaperone regulation of ribonucleotide reductase

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.

Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer

“…These results indicate that RRM2 may be a master driver of the aggressive subtypes PCS1 and luminal B by directly or indirectly regulating the expression of critical genes. Ribonucleotide reductase inhibitors have been developed for cancer treatment (Knighton et al, 2018), and we previously reported the potency of the novel RRM2 inhibitor COH29 in prostate cancer (Mazzu et al, 2019). In this study, we confirmed that inhibiting RRM2 activity by siRNA or small molecule (COH29) specifically targets PCS1 and luminal B genes (Fig.…”

Not quite the SSAme: unique roles for the yeast cytosolic Hsp70s

“…The Ssa proteins are activated by a large number of J-protein and NEF co-chaperones; binding selectivity and affinity of these to each Ssa remains undetermined. Large-scale analysis of Hsp70 isoform interactomes by high-resolution mass spectrometry of the type seen in (Truman et al 2012(Truman et al , 2015aKnighton et al 2019) would confirm that even the small amino acid differences present in Hsp70 isoforms can greatly impact co-chaperone and client-binding specificity. The Ssa proteins are highly conserved.…”

Chemogenomic screening identifies the Hsp70 co-chaperone DNAJA1 as a hub for anticancer drug resistance

“…This increased potency may be related to the destabilization of clients that are the target of these small molecules. For example, Hsp70 activates many proteins involved in the DNA damage response and DNA repair pathways (DDR), including ATM, APE1, PARP1, XRCC1 29 . Recently, studies from our group have established roles for both Hsp70 and DNAJA1 in stability of the RNR complex 8 , 29 , 30 .…”