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

• Fission yeast HMG box proteins Nht1 and Hap2 confer doxorubicin resistance.
• Doxorubicin induces Rhp54 foci formation in wild-type cells.
• Rhp54 foci formation is attenuated in the absence of Nht1 or Hap2.
• Nht1 and Hap2 are epistatic with DNA repair factors that ensure cell viability.
• Nht1 acts synergistically with transcription and chromosome segregation DXR factors.

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.