Telomere maintenance by Werner syndrome family proteins.

描述（由申请人提供）：我们将探索端粒生物学和疾病之间的联系，在沃纳早衰综合征，使用酵母和培养的人类细胞作为模型系统。端粒缩短伴随着人类衰老，但在人类衰老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综合征的特征在于衰老的过早特征和癌症的升高率，并且是由RecQ家族解旋酶/核酸外切酶WRN的丢失引起的。越来越多的证据表明，Werner细胞具有端粒缺陷，这可能导致过早衰老和癌症发病率升高，WRN（和其他RecQ解旋酶）可能在修复缩短的端粒中发挥作用。我们将解剖的酵母RecQ同源物，Sgslp，在端粒维护的既定作用。我们将绘制Sgslp的结构域，在缺乏端粒酶的酵母细胞中，需要防止快速衰老和端粒缩短，以及衰老幸存者的缺陷。我们将测试替代机制来解释这些缺陷，包括重组或端粒G-DNA结构形成中的缺陷。我们还将筛选与Sgslp在端粒维持中合作的其他遗传因子，包括衰老的重组依赖性幸存者的产生。酵母研究揭示的机制在人类细胞中的作用，特别是涉及同源重组的机制，将通过在衰老的人类培养细胞中进行实验来测试，包括WRN突变的细胞。这些研究应该阐明WRN在人类端粒中的功能，并提高对端粒在自然人类衰老和癌症中作用的理解。

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.