Chromosomal death due to misincorporation of wrong material into DNA

癌症和细菌感染是由不需要的细胞的不受控制的增殖引起的。 生物体内的类型。有效的治疗针对这些关键和特定的部分， 不需要的细胞，在生物体的旁观者细胞中不存在。一个成功的战略， 癌症或感染是针对不需要的细胞的复杂DNA代谢， 他们的染色体死亡，-一个神秘的现象，其机制仍然是 完全不清楚染色体死亡是指染色体周期不能继续， 复制周期和驱动细胞周期的遗传信息的分离。的 染色体周期被染色体损伤所阻断-DNA损伤是如此复杂 而且有害，它们会破坏整个染色体。典型的染色体损伤是 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。我们有目的地寻找 并表征诱导不可修复的染色体损伤的条件， 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个这样的条件的表征：（i） 胸腺嘧啶饥饿;（ii）有毒RNA掺入DNA。在描述染色体时- 相关的致命现象，我们实行三管齐下的办法。一方面我们 识别最戏剧性的物理读数;另一方面，我们识别最 有趣的突变体表型。分析的第三个方面是看 从基因组的角度来看。我们的第一个具体目标将解决遗传和 胸腺嘧啶饥饿的代谢方面的关系，其三个不同的阶段。第二 具体的目标将表征在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综合表征 染色体DNA内的意外RNA核苷酸毒性。结合最 与最有趣的突变体和最引人注目的 基因组模式应该产生一个全面的三维图像的现象，在遗传/ 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.