Understanding how genome stability is maintained in response to chromosomal breaks.

了解如何在应对染色体断裂时维持基因组稳定性。

• 批准号: MC_UU_00001/4
• 负责人: Timothy Humphrey
• 金额: $ 316.77万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00001%2F4
• 关键词: Understanding; how; genome; stability; maintained

DNA is wrapped around proteins called histones. Histones are modified in a number of ways that can affect cellular processes. We found that a particular histone modification, histone H3 lysine 36 trimethylation (H3K36me3), plays a key role in promoting accurate repair of broken chromosomes using a mechanism called homologous recombination. This histone mark is also essential for restarting DNA replication after exposure to replication stress, which is commonly observed in cancer cells. Moreover, we found a way to specifically target cancer cells which have lost this histone mark, using a drug (AZD1775), which is already in Phase II clinical trials. Our approach has now entered clinical trials. We plan to determine how H3K36me3 maintains viability in response to replication stress (Aim 1); how it promotes homologous recombination repair (Aim 2); and to further translate these findings into the clinic (Aim 3). We predict this work will advance our understanding of how H3K36me3 maintains genome stability in response to replication stress, and ionizing radiation; and will improve the targeting of cancers in which this histone mark is frequently depleted, including high-grade pediatric gliomas (>50%), metastatic renal carcinomas (~60%), for which prognosis is poor, and potentially other cancer types.

DNA被一种叫做组蛋白的蛋白质包裹着。组蛋白可以通过多种方式进行修饰，从而影响细胞过程。我们发现一种特殊的组蛋白修饰，组蛋白H3赖氨酸36三甲基化（H3K36me3），在通过一种称为同源重组的机制促进断裂染色体的准确修复中起关键作用。这种组蛋白标记对于暴露于复制应激后重新开始DNA复制也很重要，这在癌细胞中很常见。此外，我们发现了一种专门针对失去这种组蛋白标记的癌细胞的方法，使用一种已经处于II期临床试验的药物（AZD1775）。我们的方法现已进入临床试验阶段。我们计划确定H3K36me3如何在应对复制应激时保持活力（目的1）；如何促进同源重组修复（Aim 2）；并进一步将这些发现转化为临床应用（目标3）。我们预测这项工作将促进我们对H3K36me3如何在复制应激和电离辐射下维持基因组稳定性的理解；并且将提高这种组蛋白标记经常缺失的癌症的靶向性，包括高级别儿童胶质瘤（50%），转移性肾癌（60%），预后较差，以及潜在的其他癌症类型。

项目成果

Using Pulsed-Field Gel Electrophoresis to Analyze Schizosaccharomyces pombe Chromosomes and Chromosomal Elements.

使用脉冲场凝胶电泳分析粟酒裂殖酵母染色体和染色体元素。

• DOI: 10.1101/pdb.prot092023
• 发表时间: 2018
• 期刊: Cold Spring Harbor protocols
• 作者: Pai CC

Analysis of DNA Metabolism in Fission Yeast

裂殖酵母 DNA 代谢分析

• DOI: 10.1101/pdb.top079863
• 发表时间: 2018
• 期刊: Cold Spring Harbor Protocols
• 作者: Antequera F

An essential role for dNTP homeostasis following CDK-induced replication stress

• DOI: 10.1242/jcs.226969
• 发表时间: 2019-03-01
• 期刊: JOURNAL OF CELL SCIENCE
• 影响因子: 4
• 作者: Pai，Chen-Chun;Hsu，Kuo-Feng;Humphrey，Timothy C.
• 通讯作者: Humphrey，Timothy C.

DNA Double-Strand Break Repair Assay.

DNA 双链断裂修复测定。

• DOI: 10.1101/pdb.prot092031
• 发表时间: 2018
• 期刊: Cold Spring Harbor protocols
• 作者: Pai CC

Nucleoporin 54 contributes to homologous recombination repair and post-replicative DNA integrity.

• DOI: 10.1093/nar/gky569
• 发表时间: 2018-09-06
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Rodriguez-Berriguete G;Granata G;Puliyadi R;Tiwana G;Prevo R;Wilson RS;Yu S;Buffa F;Humphrey TC;McKenna WG;Higgins GS
• 通讯作者: Higgins GS