Telomeric Function in Aging Syndromes

描述（由申请人提供）：端粒是线性染色体的天然末端。在哺乳动物中，它们由重复序列TTAGGG组成，在小鼠中可延伸至150 kb，在人类中可延伸至15对。端粒的最末端由富含G的3'链的单链突出端组成，其可以长达300个核苷酸。许多蛋白质与端粒重复序列特异性结合。端粒重复序列结合因子TRF1和TRF2与染色体末端的双链区域结合，并在那里与它们的相互作用蛋白质形成复合物。TRF 1相互作用因子是Tin2、端锚聚合酶1和2以及Pot1，所有这些都与端粒长度调节有关。TRF2与MRN复合物hRapl相互作用，并且已经被认为在端粒保护中起主要作用。沃纳综合征是一种节段性过早衰老疾病，患者在30至40岁时已经显示出许多老年迹象。此外，患者的癌症发病率很高，沃纳综合征细胞经常显示基因组不稳定性。布卢姆综合征是由与沃纳蛋白相关的解旋酶突变引起的，患者还患有过早衰老和癌症。我们的初步数据表明，沃纳综合征可能是由端粒复制功能障碍引起的，并首次将端粒功能障碍与这些衰老综合征联系起来。在AIM1中，我们将分析Werner综合征细胞中的端粒结构，研究端粒酶在端粒拯救和维护中的作用，并确定端粒与DNA损伤信号之间的关系。AIM2专注于WRN和其他RecQ解旋酶在富G结构复制中的作用，以及WRN与端粒蛋白的相互作用。在AIM 3中，我们计划研究WRN与RecQ解旋酶家族其他成员在复制中的冗余。此外，我们将研究RecQ解旋酶依赖性端粒功能障碍对这些综合征中基因组不稳定性的影响。相关性：沃纳综合征是一种过早衰老的疾病，癌症的发生率很高。在这里，我们的目的是调查端粒功能在综合征中的作用，并阐明端粒复制，衰老和癌症在沃纳综合征之间的联系。

DESCRIPTION (provided by applicant): Telomeres are the natural ends of linear chromosomes. In mammals they consist of the repeated sequence TTAGGG that can stretch for up to 150 kb in mice, and 15 kilobase pairs in humans. The very end of the telomeres is made up of a single stranded overhang of the G rich 3' strand that can be up to 300 nucleotides long. A number of proteins bind specifically to the telomeric repeats. The telomeric repeat binding factors TRF1 and TRF2 bind to the double stranded regions of the chromosome ends, and form complexes there with their interacting proteins. TRF1 interacting factors are Tin2, tankyrase 1 and 2 and Pot1, all of which have been implicated in telomere length regulation. TRF2 interacts with the MRN complex hRapl, and has been suggested to play a major role in telomere protection. Werner Syndrome is a segmental premature aging disorder, where patients show many signs of old age already with 30 to 40 years. Additionally patients have a high incidence of cancer, and Werner Syndrome cells frequently show genome instability. Blooms syndrome is caused by mutations in a helicase related to the Werner protein, and patients also suffer from premature aging and cancer. Our preliminary data suggest that Werner syndrome could be caused by a dysfunction in telomere replication, and for the first time links telomere dysfunction to these aging syndromes. In AIM1 we will analyze telomere structure in Werner Syndrome cells, investigate the role of telomerase in telomere rescue and maintenance, and define the relationship between telomeres and DNA damage signals. AIM2 focuses on the role of WRN and other RecQ helicases in replication of G rich structures, as well as the interaction of WRN with telomeric proteins. In AIM 3 we plan to study the redundancy of WRN with other members of the RecQ helicase family on replication. Furthermore we will investigate the effects of RecQ helicase dependent telomere dysfunction on genome instability in these syndromes. Relevance: Werner Syndrome is a premature aging disease with a high frequency of cancer. Here we aim to investigate the role of telomere function in the syndrome, and to elucidate the connection between telomere replication, aging and cancer in Werner Syndrome.