Telomere maintenance by Werner syndrome family proteins.

描述（由申请人提供）：我们将以酵母和培养的人类细胞为模型系统，探索端粒生物学与Werner早衰综合征疾病之间的联系。端粒缩短伴随着人类衰老，但起着不确定的因果作用。相反，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升高，是由recq家族解旋酶/外切酶WRN的缺失引起的。越来越多的证据表明，Werner细胞存在端粒缺陷，这可能导致过早衰老和癌症发病率升高，而WRN（和其他RecQ解旋酶）可能在端粒缩短的修复中起作用。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结构域，在缺乏端粒酶的酵母细胞中，这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。我们将测试其他机制来解释这些缺陷，包括端粒重组或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素，包括衰老的重组依赖幸存者的产生。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，将通过在人类培养细胞中进行衰老实验来测试，包括那些具有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认识。

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.