Telomere maintenance by Werner syndrome family proteins.

描述(由申请人提供)：我们将使用酵母和培养的人类细胞作为模型系统，探索端粒生物学与沃纳早衰综合征疾病之间的联系。端粒缩短伴随着人类衰老，但在人类衰老过程中起着不确定的因果作用。相比之下，很明显，预防端粒缩短是大多数癌症生长所必需的。Werner综合征的特点是过早衰老和癌症发病率增加，由RecQ家族解旋酶/核酸外切酶WRN丢失引起。越来越多的证据表明，Werner细胞存在端粒缺陷，这可能是导致过早衰老和癌症发病率上升的原因之一，而WRN(和其他RecQ解旋酶)可能在端粒缩短的修复中发挥作用。我们将剖析酵母RecQ同源物Sgslp在端粒维持中的既定作用。我们将绘制Sgslp的结构域，在缺乏端粒酶的酵母细胞中，这些结构域是防止快速衰老和端粒缩短所必需的，以及衰老幸存者的缺陷。我们将测试解释这些缺陷的替代机制，包括重组缺陷或端粒G-DNA结构的形成。我们还将筛选与SGSLP在端粒维持方面合作的其他遗传因素，包括衰老依赖重组幸存者的产生。酵母研究揭示的机制在人类细胞中的作用，特别是那些涉及同源重组的机制，将通过在老化的人类培养细胞中进行实验来测试，包括那些WRN突变的细胞。这些研究将阐明WRN在人类端粒中的功能，并提高对端粒在人类自然衰老和癌症中的作用的理解。

DESCRIPTION (provided by applicant): We will explore connections between telomere biology and disease in the Werner premature aging syndrome, using yeast and cultured human cells as model systems. Telomere shortening accompanies but plays an uncertain causal role in human aging. In contrast, it is clear that prevention of telomere shortening is required for the growth of most cancers. Werner syndrome is characterized by premature features of aging and by elevated rates of cancer, and is caused by loss of the RecQ-family helicase/exonuclease WRN. Evidence is accumulating that Werner cells have telomere defects, which might contribute to the premature aging and elevated cancer incidence, and WRN (and other RecQ helicases) may function in the repair of shortened telomeres. We will dissect the established role of the yeast RecQ homologue, Sgslp, in telomere maintenance. We will map the domains of Sgslp that, in yeast cells lacking telomerase, are required to prevent rapid senescence and telomere shortening, as well as defects in survivors of senescence. We will test alternative mechanisms to explain these defects, including defects in recombination or the formation of G-DNA structures at telomeres. We will also screen for other genetic factors that cooperate with Sgslp in telomere maintenance, including the generation of recombination dependent survivors of senescence. The role in human cells of the mechanisms revealed by studies in yeast, particularly those involving homologous recombination, will be tested by performing experiments in senescing human cultured cells, including those with mutations in WRN. These studies should illuminate the function of WRN at human telomeres and improve understanding of the role of telomeres in natural human aging and cancer.