Telomeric dysfunction and the premature aging and cancer-prone disease Werner syn

描述（申请人提供）：端粒是染色体末端的特化结构，对基因组稳定性和细胞复制能力至关重要。维持适当的端粒结构和长度允许细胞继续分裂。然而，体内大多数复制细胞不表达维持酶端粒酶，并逐渐失去端粒DNA，最终达到触发细胞衰老和/或凋亡的极短端粒长度。从理论上讲，组织中衰老细胞的显著积累或凋亡细胞的丢失发生在生命的后期，并且可能是某些正常衰老特征发展的基础。然而，目前缺乏对正常个体中端粒功能障碍、细胞衰老和可能的衰老表型之间关系的坚实支持。过早衰老疾病Werner综合征（WS）表现出许多有害的衰老特征（包括癌症、动脉粥样硬化、骨质疏松症、白内障、糖尿病和高血压）的早期发作和频率增加，其由单一蛋白WRN的功能丧失引起。来源于WS患者的细胞显示端粒异常和显著的过早细胞衰老，这是通过端粒酶的先前表达来防止的。来自几个实验室（包括我们的）的调查表明，WRN在端粒维护中起作用，可能与端粒蛋白TRF 2协调。因此，WS是研究端粒维持、细胞衰老、细胞凋亡和特定衰老特征发展之间关系的极好模型。该提案将研究WRN（与TRF 2和其他端粒因子一起）对相关端粒DNA结构的生物化学活性，并确定其在端粒代谢中的功能期间的蛋白质伴侣，特别强调端粒复制。此外，在用选定的DNA损伤剂长期处理期间，将检查正常和WS细胞中的端粒动力学（复制动力学和长度改变）和细胞衰老。这些研究将阐明WRN的端粒功能，并确定端粒区域的持续DNA损伤是否会加剧WS细胞中端粒随时间的丢失，并为端粒功能障碍在WS和正常衰老中特定年龄相关特征的发展中的作用提供进一步的支持。因此，这项建议将涉及和检查在基因组维护和抑制某些衰老表型以及癌症的基本机制。公共卫生相关性：这项提议研究了一种特殊的蛋白质WRN在维持染色体末端（也称为端粒）中的作用。当人类WRN的功能丧失时（在遗传性疾病Werner综合征中），所产生的端粒异常触发细胞衰老或细胞死亡，并及时导致受影响个体的衰老特征和癌症的早期发展。通过研究Werner综合征和WRN在端粒代谢中的作用，该提案将有助于了解抑制特定衰老特征和癌症发展的基本细胞机制。

DESCRIPTION (provided by applicant): Telomeres are specialized structures on chromosome ends that are essential for genome stability and cellular replicative capacity. Maintenance of proper telomere structure and length allows continued cell division. However, most replicating cells in the body do not express the maintenance enzyme telomerase and gradually lose telomeric DNA, eventually reaching a critically short telomere length that triggers cellular senescence and/or apoptosis. Theoretically, significant accumulation of senescent cells or loss of apoptotic cells in tissues occurs late in life and may underlie development of certain normal aging characteristics. However, solid support for the relationship between telomere dysfunction, cellular senescence and possible aging phenotypes in normal individuals is currently lacking. The premature aging disease Werner syndrome (WS) that shows early onset and increased frequency of many deleterious aging features (including cancer, atherosclerosis, osteoporosis, cataracts, diabetes, and hypertension) is caused by loss of function of a single protein, WRN. Cells derived from WS patients show telomeric abnormalities and a dramatic premature cellular senescence that is prevented by prior expression of telomerase. Investigations from several laboratories (including ours) indicate that WRN functions in telomere maintenance, possibly in coordination with the telomeric protein TRF2. Thus, WS is an excellent model for studying the relationships between telomere maintenance, cellular senescence, apoptosis, and development of specific aging characteristics. This proposal will examine the biochemical activities of WRN (in conjunction with TRF2 and other telomeric factors) on relevant telomeric DNA structures and determine its protein partners during its function in telomere metabolism with specific emphasis on telomeric replication. In addition, telomere dynamics (replication kinetics and length alterations) and cellular senescence in normal and WS cells will be examined during chronic treatment with selected DNA damaging agents. These studies will clarify the telomeric function of WRN and determine whether persistent DNA lesions in telomeric regions exacerbate telomere loss over time in WS cells compared to normal cells, and provide further support to the role of telomere dysfunction in the development of specific age-related characteristics in WS as well as in normal aging. Thus, this proposal will implicate and examine basic mechanisms at work in genome maintenance and suppression of certain aging phenotypes as well as cancer. PUBLIC HEALTH RELEVANCE: This proposal examines the role of a specific protein, WRN, in the maintenance of chromosome ends, otherwise known as telomeres. When the function of human WRN is lost (in the hereditary disease Werner syndrome), the resulting telomeric abnormalities trigger cell senescence or cell death and, in time, cause early development of aging features and cancer in affected individuals. By investigating Werner syndrome and the role of WRN in telomere metabolism, this proposal will help understand basic cellular mechanisms that act to suppress development of specific aging characteristics as well as cancer.