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

DNA包裹在被称为组蛋白的蛋白质周围。组蛋白以多种方式修饰，可以影响细胞过程。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（H3 K36 me 3），在使用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着关键作用。这种组蛋白标记对于暴露于复制应激后重新启动DNA复制也是必不可少的，这在癌细胞中常见。此外，我们发现了一种方法，可以特异性地靶向已经失去这种组蛋白标记的癌细胞，使用一种药物（AZD 1775），该药物已经在II期临床试验中。我们的方法已经进入临床试验。我们计划确定H3 K36 me 3如何在复制应激中保持活力（目标1）;它如何促进同源重组修复（目标2）;并进一步将这些发现转化为临床（目标3）。我们预测这项工作将促进我们对H3 K36 me 3如何维持基因组稳定性以应对复制应激和电离辐射的理解;并将改善这种组蛋白标记经常耗尽的癌症的靶向，包括高级别儿科胶质瘤（>50%），转移性肾癌（约60%），预后差，以及潜在的其他癌症类型。

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.