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题目:On the novel mechanism and selectivity of anthracycline drugs

报告人:宝旭 大学医学中心

时间:2018年95日(周三)13:30

地点:新民校区第二教学楼2103室

报告人简介:

2013年博士毕业于荷癌症研究所,2013-2014年在荷癌症研究所从事博士后工作,2014年至2018,在斯坦福大学医学院遗传系从事博士后工作。2017年10月至今在荷大学医学中心化学和胞生物学系担任助理教授。博士工作期,基于蒽疗药物,发现并定了一种全新的物作用机制-物直接介导组蛋白从染色的脱离,从而影响胞的表冠遗传学和DNA损伤的修复。相关研究果以第一作者或共同通作者表在《Nature Communications》, Cancer Research ,Nature Chemical Biology 》等志。博士后工作期两种高通量筛选统对基因编码调节区的功能行研究。博士科研期间获得荷Antoni van Leeuwenhoek Prize和国家秀自留学生学金。实验室被荷LUMC Gisela Thier FellowshipKWF Young Investigator Award助。

报告摘要:

DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. We identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. Histone eviction attenuated DNA repair and deregulated the transcriptome in cancer cells and organs such as the heart, and can drive apoptosis of topoisomerase-negative acute myeloid leukaemia blasts in patients. We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with important consequences for DNA damage responses, epigenetics, transcription, side effects and cancer therapy. In addition, we performed genome-wide high-resolution mapping of chemotherapeutic effects of various topoisomerase I and II (TopoI and II) inhibitors and integrated this mapping with established maps of genomic or epigenomic features to show their activities in different genomic regions. We show that aclarubicin, has a different genomic specificity and evicts histones from H3K27me3-marked heterochromatin, with consequences for diffuse large B-cell lymphoma cells with elevated levels of H3K27me3. Modifying anthracycline structures may yield compounds with selectivity for different genomic regions and activity for different tumor types.

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