Makorin-1 Control of Telomerase

描述（由申请人提供）：概要端粒酶活性和端粒稳态的调节在生长控制中是根本重要的。新的数据表明，人类端粒酶活性受泛素化的调控。具体而言，端粒酶的催化亚基hTERT被泛素后修饰并定向至26 S蛋白酶体进行降解。一个特异性的E3连接酶基因已经从人类中被鉴定和克隆。这种连接酶与一个被称为makorin-1的保守而古老的基因相同，makorin-1是最近发现的功能未知的基因家族的创始成员。MKRN 1编码一个RING-锌指蛋白，催化泛素与hTERT的连接。在癌细胞中高水平的MKRN 1表达导致端粒DNA侵蚀和端粒酶活性的降低，如通过TRAP测定所测量的。为了了解hTERT调控的这一新途径，计划了一系列目标，以详细研究癌细胞中过度表达和表达不足的MKRN 1的后果。本研究的最终目标是确定癌症治疗干预的新靶点，并探索蛋白酶体途径如何与端粒稳态途径在机械上相交。端粒是由重复DNA序列（TTAGGG）加密并由端粒酶维持的染色体的物理末端。我们有新的证据表明，人类端粒酶是由泛素/蛋白酶体途径调节，我们已经克隆了一个端粒酶杀手基因称为MKRN 1。由于大多数肿瘤细胞不适当地表达端粒酶，端粒酶失活途径在设计干预癌症的新方法中具有临床意义。

DESCRIPTION (provided by applicant): SUMMARY Regulation of telomerase activity and telomere homeostasis is fundamentally important in growth control. New data in this proposal suggest that human telomerase activity is regulated by ubiquitylation. Specifically, the catalytic subunit of telomerase, hTERT, is post-translationally modified by ubiquitin and directed to the 26S proteasome for degradation. A specific E3 ligase gene has been identified and cloned from humans. This ligase is identical to a well conserved and ancient gene called makorin-1, the founding member of a recently discovered gene family of unknown function. MKRN1 encodes a RING-zinc finger protein that catalyzes the ligation of ubiquitin to hTERT. High levels of MKRN1 expression in cancer cells lead to telomere DNA erosion and a reduction in telomerase activity as measured by the TRAP assay. In order to understand this new pathway for hTERT regulation, a series of objectives are planned to examine in detail the consequences of over and under-expressing MKRN1 in cancer cells. The ultimate goal of this research is to identify novel targets for therapeutic intervention in cancer and to explore how the proteasome pathway intersects mechanistically with the telomere homeostatic pathway. Telomeres are the physical ends of chromosomes encrypted by a repeat DNA sequence (TTAGGG) and maintained by telomerase. We have new evidence that human telomerase is regulated by the ubiquitin/proteasome pathway and we have cloned a telomerase killer gene called MKRN1. Since most tumor cells inappropriately express telomerase, a telomerase inactivation pathway is of clinical significance in designing new ways to intervene in cancer.