Two fission yeast high mobility group box proteins in the maintenance of genomic integrity following doxorubicin insult.

Drug resistance is a challenge in chemotherapy, and, to date, there has been little resolution as to how it is induced. We previously isolated a host of doxorubicin resistance (DXR) genes in fission yeast and here we investigate the regulation of this resistance through two high mobility group (HMG) motif-containing DXR proteins, Nht1 and Hap2. The concurrent deletion of nht1 and hap2 did not confer cumulative sensitivity to doxorubicin, indicating that these factors cooperate closely in similar epistatic groups. We show that doxorubicin treatment resulted in the subcellular reorganization of Rhp54, a homologous recombination-dependent DNA damage repair protein. The disruption of either nht1 or hap2 attenuated Rhp54-foci formation, suggesting that these factors modulate the repair of doxorubicin-induced DNA lesions via the recruitment of homologous recombination machinery. Epistatic analyses further confirmed that Nht1 and Hap2 act in similar functional groups with complexes related to DSB repair but act synergistically with factors that regulate transcription and chromosome segregation. Overall, this work shows the molecular crosstalk coordinated by HMG proteins in conferring doxorubicin resistance in fission yeast.

Cellular robustness conferred by genetic crosstalk underlies resistance against chemotherapeutic drug doxorubicin in fission yeast.

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.