Two fission yeast high mobility group box proteins in the maintenance of genomic integrity following doxorubicin insult.
Two fission yeast high mobility group box proteins in the maintenance of genomic integrity following doxorubicin insult.
复制标题
两种裂殖酵母高迁移率族盒蛋白在阿霉素损伤后维持基因组完整性。
DOI：
10.1016/j.gene.2015.02.041
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发表时间：
2015
期刊：
影响因子：
3.5
通讯作者：
Chen ES
中科院分区：
文献类型：
--
作者：
Tang MY;Guo H;Nguyen TT;Low LS;Jackson RA;Yamada T;Chen ES
耐药性是化疗中的一个挑战，迄今为止，对于如何诱导耐药性几乎没有解决方案。我们之前在裂殖酵母中分离了许多阿霉素抗性（DXR）基因，在这里我们通过两个含有高迁移率基团（HMG）基序的DXR蛋白Nht1和Hap2研究了这种抗性的调节。同时删除nht1和hap2并没有赋予对阿霉素的累积敏感性，表明这些因素在相似的上位组中密切合作。我们发现阿霉素处理导致 Rhp54（一种同源重组依赖性 DNA 损伤修复蛋白）的亚细胞重组。 nht1或hap2的破坏减弱了Rhp54-foci的形成，表明这些因子通过同源重组机制的募集来调节阿霉素诱导的DNA损伤的修复。上位分析进一步证实，Nht1 和 Hap2 在与 DSB 修复相关的复合物中发挥相似的功能，但与调节转录和染色体分离的因子协同作用。总体而言，这项工作显示了 HMG 蛋白协调的分子串扰赋予裂殖酵母阿霉素抗性。
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 ofnht1andhap2did 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 eithernht1orhap2attenuated 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.