Cellular Robustness Conferred by Genetic Crosstalk Underlies Resistance against Chemotherapeutic Drug Doxorubicin in Fission Yeast

Abstract

Doxorubicin is an anthracycline antibiotic that is among one of the most commonly used chemotherapeutic agents in the clinical setting. The usage of doxorubicin is faced with many problems including severe side effects and chemoresistance. To overcome these challenges, it is important to gain an understanding of the underlying molecular mechanisms with regards to the mode of action of doxorubicin. To facilitate this aim, we identified the genes that are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe. We further demonstrated interplay between factors controlling various aspects of chromosome metabolism, mitochondrial respiration and membrane transport. In the nucleus we observed that the subunits of the Ino80, RSC, and SAGA complexes function in the similar epistatic group that shares significant overlap with the homologous recombination genes. However, these factors generally act in synergistic manner with the chromosome segregation regulator DASH complex proteins, possibly forming two major arms for regulating doxorubicin resistance in the nucleus. Simultaneous disruption of genes function in membrane efflux transport or the mitochondrial respiratory chain integrity in the mutants defective in either Ino80 or HR function resulted in cumulative upregulation of drug-specific growth defects, suggesting a rewiring of pathways that synergize only when the cells is exposed to the cytotoxic stress. Taken together, our work not only identified factors that are required for survival of the cells in the presence of doxorubicin but has further demonstrated that an extensive molecular crosstalk exists between these factors to robustly confer doxorubicin resistance.

Calcium modulation of doxorubicin cytotoxicity in yeast and human cells

“…We next grouped the DCR genes according to ontological pathways, with eight ontological groups identified: DNA repair (four genes: rhp51 + , rad32 + , rad24 + and caf1 + ); gene transcription (six genes: gcn5 + , ngg1 + , nrm1 + , yox1 + , abo1 + and tup12 + ); chromatin remodeling (five genes: hap2 + , ada2 + , arp42 + , nht1 + and est1 + ); chromosome segregation (four genes: duo1 + , spc19 + , dad2 + and dad5 + ); RNA processing (one gene: spbc19g7.10c ); membrane transport (four genes: vph2 + , rav1 + , vps35 + and vps901 + ); signaling (two genes: mfm1 + and git1 + ); and one unknown group ( spbc16h5.13 ) (Tay et al . ) (Fig. A).…”

“…; Tay et al . ). An additional two smaller clusters were obtained for the DCR genes related to vacuolar transport (Vps35 and Vps901) (Iwaki et al .…”

“…; Tay et al . , ) (Figs , S1 in Supporting Information). Two replicates of the calcium sensitivity test were carried out for each strain (Fig.…”

“…) and previously reported ontological classifications were used to categorize the genes of the calcium‐sensitive mutants (Tay et al . ). String version 9.1 was used to determine protein–protein networks within the gene sets (Franceschini et al .…”

Identification of Coq11, a New Coenzyme Q Biosynthetic Protein in the CoQ-Synthome in Saccharomyces cerevisiae

“…Interestingly, YLR290C was found to have a genetic correlation with both COQ2 and COQ10 in high throughput analyses (55). YLR290C was also identified along with COQ1, COQ2, COQ3, COQ4, COQ6, COQ7, and COQ10 as part of a set of mitochondrial genes required for doxorubicin resistance (76).…”