Telomere maintenance by Werner syndrome family proteins.

我们将探讨端粒生物学和疾病之间的联系，在维尔纳过早老化， 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， 在人类衰老中扮演着不确定的因果角色。相反，很明显，防止端粒缩短 是大多数癌症生长所必需的Werner综合征的特点是过早的特征， 衰老和癌症发病率升高，并且是由RecQ家族解旋酶/核酸外切酶的缺失引起的 WRN。越来越多的证据表明，沃纳细胞有端粒缺陷，这可能有助于 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。我们将剖析酵母RecQ同源物Sgslp的既定作用， 端粒维持我们将绘制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，以及缺陷的幸存者， 衰老我们将测试替代机制来解释这些缺陷，包括 重组或端粒处G-DNA结构的形成。我们还将筛查其他遗传 在端粒维持中与Sgslp合作的因素，包括重组的产生- 依赖衰老的幸存者研究揭示的机制在人类细胞中的作用， 酵母，特别是那些涉及同源重组的酵母，将通过进行以下实验进行测试： 衰老的人类培养细胞，包括那些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中作用的理解。 衰老和癌症

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 surivivors 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 recombintation, 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.