Telomere maintenance by Werner syndrome family proteins

描述（由申请人提供）：我们将使用小鼠和酵母作为模型系统，探索端粒生物学与Werner过早衰老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。沃纳综合征和布卢姆综合征的特征是过早衰老和癌症发病率升高。这些综合征分别由相关RecQ家族解旋酶WRN和BLM的丢失引起。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，需要防止快速衰老和端粒缩短，以及衰老存活者的缺陷。我们将测试其他机制来解释这些缺陷，包括不适当的重组或端粒处G-DNA结构的形成。我们还将筛选与Sgslp在端粒维持中合作的其他遗传因子。我们还将研究WRN和BLM在由于端粒酶基因失活而缩短端粒的小鼠中的功能。我们将询问缺乏端粒酶以及WRN和BLM的小鼠是否比单纯缺乏端粒酶或WRN和BLM的小鼠更早，更深刻甚至不同的缺陷。将检查高度增殖组织（包括性腺、胃肠道系统和皮肤）中的萎缩和细胞凋亡。端粒缩短率、细胞遗传学不稳定性和辐射敏感性将在有或无功能性WRN和BLM的缺乏端粒酶的组织和细胞中进行比较。此外，WRN和BLM在使用重组而不是端粒酶维持其端粒的细胞中的作用将被探索。这些研究应该阐明WRN和BLM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 telomeres biology and diseases in the Werner premature aging syndrome, using mouse and yeast 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 and Bloom syndrome are characterized by premature features of aging and by elevated rates of cancers. The syndromes are caused by loss of the related RecQ-family helicases WRN and BLM, respectively. 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 maintenace. 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 inappropriate 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. We will also examine the function of WRN and BLM in mice that have shortened telomeres due to genetic inactivation of telomerase. We will ask whether mice that lack telomerase and WRN and BLM together develop earlier, more profound or even different defects than mice that simply lack telomerase alone or WRN and BLM together. Atrophy and apoptosis in highly proliferative tissues, including the gonads, gastrointestinal system and skin, will be examined. Rates of telomere shortening, cytogenetic instability, and radiation sensitivity will compared in tissues and cells lacking telomerase in the presence or absence of functional WRN and BLM. Additionally, the role of WRN and BLM in cells that maintain their telomeres using recombination, rather than telomerase, will be explored. These studies should illuminate the function of WRN and BLM at human telomeres and improve understanding of the role of telomeres in natural human aging and cancer.