Tang Ming Yi Richard, Guo Huifang, Nguyen Thi Thuy Trang, Low Liy Sim, Jackson Rebecca A, Yamada Takatomi, Chen Ee Sin
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; National University Health System (NUHS), Singapore.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Gene. 2015 May 10;562(1):70-5. doi: 10.1016/j.gene.2015.02.041. Epub 2015 Feb 17.
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.
耐药性是化疗中的一个挑战，迄今为止，关于其如何产生的问题几乎没有得到解决。我们之前在裂殖酵母中分离出了许多阿霉素抗性（DXR）基因，在此我们通过两种含有高迁移率族（HMG）基序的DXR蛋白Nht1和Hap2来研究这种抗性的调控机制。同时缺失nht1和hap2并不会使细胞对阿霉素产生累积敏感性，这表明这些因子在相似的上位性组中密切协作。我们发现阿霉素处理会导致Rhp54（一种依赖同源重组的DNA损伤修复蛋白）的亚细胞重排。nht1或hap2的缺失会减弱Rhp54焦点的形成，这表明这些因子通过招募同源重组机制来调节阿霉素诱导的DNA损伤的修复。上位性分析进一步证实，Nht1和Hap2与DSB修复相关复合物在相似的功能组中发挥作用，但与调节转录和染色体分离的因子协同作用。总体而言，这项工作展示了HMG蛋白在裂殖酵母中赋予阿霉素抗性过程中所协调的分子串扰。
