Responses to Telomere Loss

 描述（由申请人提供）：这项工作的长期目标是了解生物体用于确保基因组完整性从一代到一代和从细胞到细胞得以维持的机制。基因组会受到各种形式的损伤，并进化出各种修复损伤或科普失败的机制。 为了维持染色体的稳定性，真核生物的线性染色体必须被端粒覆盖。单个端粒的丢失是一种特别具有挑战性的基因组损伤形式，并且最常导致细胞凋亡，而不是成功修复。已知这种类型的损伤有两种形式的修复：愈合，指的是在染色体的非端粒末端添加新的端粒;或断裂诱导复制（BIR），其中断裂的染色体从另一条染色体复制信息以取代它缺失的末端。这两种类型的修复都与基因组的改变有关。由于这通常是不可取的，这些维修模式可被视为“最后手段的维修”。 本研究将探讨端粒缺失对生殖细胞的影响。目标是确定用于检测和消除具有这种形式损伤的细胞的遗传控制。将探讨雄性和雌性生殖系之间反应的差异。这里提出的实验还将研究BIR修复模式，这在以前的任何种系中都没有得到证实。这种类型的修复具有额外的兴趣，因为它与某些癌细胞中发现的端粒维持形式相似。

 DESCRIPTION (provided by applicant): The long-term objective of this work is to understand the mechanisms that organisms use to ensure that genome integrity is maintained from generation to generation and from cell to cell. Genomes are subject to damage in a variety of forms and have evolved a variety of mechanisms to repair damage, or to cope with failure. To maintain chromosome stability, the linear chromosomes of eukaryotes must be capped with telomeres. Loss of a single telomere is a particularly challenging form of genome damage, and most often results in apoptosis, rather than successful repair. Two forms of repair are known for this type of damage: healing, which refers to the addition of a new telomere on the non-telomeric end of a chromosome; or Break-Induced Replication (BIR), in which the broken chromosome copies information from another chromosome to replace the end that it is missing. Both types of repair are associated with alterations in the genome. Since this is generally undesirable, these modes of repair may be considered "repair of last resort". The work proposed here will investigate the germline responses to telomere loss. The goals are to identify the genetic controls that are used to detect and eliminate cells with this form of damage. Differences in the responses between male and female germlines will be explored. The experiments proposed here will also investigate the BIR mode of repair, which has not been previously demonstrated in any germline. This type of repair has additional interest because of its similarity to a form of telomere maintenance found in some cancer cells.