Telomere replication and maintenance of genome stability

描述（由申请人提供）：人类衰老和相关器官退化所涉及的分子机制和遗传途径尚不清楚。人类衰老与许多高度增殖组织的功能缺陷有关。这些组织必须不断地由组织干细胞补充，因为分化的细胞在整个生命过程中都会丢失。越来越多的证据表明，正常的人类衰老过程与干细胞功能的下降有关。因此，为了设计出方法来帮助改善正常衰老过程的病理影响，需要更好地了解干细胞功能在人类衰老过程中如何改变。使用小鼠模型和人类细胞系的研究表明，维持端粒稳态对于干细胞功能至关重要。端粒是核蛋白结构，在维持染色体完整性和基因组稳定性方面发挥着重要作用。在哺乳动物中，端粒由 TTAGGG 重复序列组成，并由端粒酶维持。端粒酶在人类体细胞中受到限制，导致端粒逐渐缩短。无法再发挥末端保护功能的功能失调端粒被 DNA 损伤修复 (DDR) 途径识别为 DNA 双链断裂。虽然端粒重复被真核生物用来解决末端复制问题并赋予染色体末端保护功能，但它们在 DNA 复制过程中造成了独特的问题，因为它们类似于脆弱位点。该提案涉及端粒生物学中一个很大程度上未被探索的领域——正确的端粒复制在维持基因组稳定性和细胞稳态方面发挥什么影响？我们的提议具有创新性，因为它解决了这样的假设：端粒无法正确复制可能与端粒酶缺陷一样重要，从而产生不稳定的基因组。

DESCRIPTION (provided by applicant): The molecular mechanisms and genetic pathways involved in human aging and associated organ degeneration are not well understood. Human aging is associated with functional defects in many highly proliferative tissues. These tissues must be continuously replenished by tissue stem cells, since differentiated cells are lost throughout life. Increasing evidence suggests that the normal human aging process is associated with a decline in stem cell function. Therefore, to devise approaches to help ameliorate the pathological effects of the normal aging process, a greater understanding of how stem cell functions are altered during human aging is required. Studies using mouse models and human cell lines point to the maintenance of telomere homeostasis as critical for stem cell function. Telomeres are nucleoprotein structures that play essential roles in maintaining chromosome integrity and genome stability. In mammals, telomeres consist of TTAGGG repetitive sequences and are maintained by the enzyme telomerase. Telomerase is limiting in human somatic cells, resulting in progressive telomere shortening. Dysfunctional telomeres that can no longer exert end-protective functions are recognized as DNA double stranded breaks by the DNA damage repair (DDR) pathway. While telomere repeats are used by eukaryotes to solve the end replication problem and confers chromosome end protective functions, they pose a unique problem during DNA replication since they resemble fragile sites. This proposal addresses a largely unexplored area of telomere biology-what impact does proper telomere replication play in the maintenance of genome stability and cellular homeostasis? Our proposal is innovative because it addresses the hypothesis that failure to properly replicate telomeres may be as important as telomerase deficiency to generate an unstable genome.