Chromosomal death due to misincorporation of wrong material into DNA

癌症和细菌感染是由有害细胞的不受控制的繁殖引起的 有机体内的类型。有效的治疗针对这些疾病的关键和特定部分 不需要的细胞，在有机体的旁观者细胞中不存在。一种成功的战斗策略 癌症或感染是以复杂的DNA代谢为靶点的不受欢迎的细胞，导致 他们的染色体死亡--一种神秘的现象，其机制仍然是 完全不清楚。染色体死亡是指无法继续染色体周期-- 驱动细胞周期的遗传信息的复制和分离的周期。这个 染色体损伤阻止了染色体周期--DNA损伤是如此复杂 而且有害的是，它们会使整个染色体失活。一种典型的染色体损伤是一种 双链DNA断裂，但最常见的染色体损伤得到有效修复 通过重组修复和各种备份的途径。我们正在有目的地寻找 以及描述导致不可修复的染色体损伤的条件，从而导致 染色体死亡，使其有可能转化为未来的治疗方法 不良细胞。本申请描述了我们对两种情况的描述：(I) 胸腺嘧啶饥饿；(Ii)有毒的RNA掺入DNA。在描述一条染色体时- 对于相关的致命现象，我们采取了三管齐下的方法。一方面，我们 确定最戏剧性的物理读数；另一方面，我们确定最 有趣的突变体表型。分析的第三个方面是查看 染色体从基因组的角度来看。我们的第一个具体目标是解决遗传和 胸腺嘧啶饥饿的代谢方面与其三个不同阶段的关系。第二 特定的目的将描述胸腺嘧啶饥饿期间染色体的物理变化。 第三个目的是对小说现象的全面刻画。 染色体DNA中意想不到的RNA核苷酸毒性。结合了最多 与最有趣的突变和最戏剧性的相关物理读数 基因组模式应该产生遗传/基因现象的全面3D图像 物理/基因组维度，产生对最复杂的 染色体死亡的机制。

Cancer and bacterial infections are caused by uncontrolled multiplication of undesired cell types within the organism. Effective treatments target critical and specific parts of these undesired cells, absent in by-stander cells of the organism. One successful strategy to fight cancer or infections is to target the complex DNA metabolism of the undesired cells, causing their chromosomal death, — a mysterious phenomenon, whose mechanisms are still completely unclear. Chromosomal death is the inability to continue chromosome cycle —the cycle of replication and segregation of genetic information that drives the cell cycle. The chromosomal cycle is blocked by chromosomal lesions — DNA lesions that are so complex and harmful, that they inactivate the entire chromosomes. A classic chromosomal lesion is a double-strand DNA break, but the most common chromosomal lesions are efficiently mended by pathways of recombinational repair and various back-ups. We are purposefully looking for and characterizing conditions that induce irreparable chromosomal lesions that cause chromosomal death, to make it possible to convert them into future treatments against undesirable cells. This application describes our characterization of two such conditions: (i) thymine starvation; (ii) toxic RNA incorporation into DNA. In characterizing a chromosome- associated lethal phenomenon, we practice a three-pronged approach. On the one hand, we identify the most dramatic physical readouts; on the other hand, we identify the most interesting phenotypes of mutants. The third arm of the analysis is to look at the chromosome from the genome perspective. Our fist specific aim will address genetic and metabolic aspects of thymine starvation in relation to its three distinct phases. The second specific aim will characterize physical changes in the chromosome during thymine starvation. The third aim is about comprehensive characterization of the novel phenomenon of the unexpected RNA nucleotide toxicity within the chromosomal DNA. Combining the most relevant physical readouts with the most interesting mutants and the most dramatic genomic patterns should yield a comprehensive 3D-picture of the phenomenon in genetic / physical / genomic dimensions, producing mechanistic insights into the most complicated mechanisms of chromosomal death.