Tombline Gregory, Millen Jonathan I, Polevoda Bogdan, Rapaport Matan, Baxter Bonnie, Van Meter Michael, Gilbertson Matthew, Madrey Joe, Piazza Gary A, Rasmussen Lynn, Wennerberg Krister, White E Lucile, Nitiss John L, Goldfarb David S
Biology Department, University of Rochester, Rochester, NY 14627, USA.
Department of Biopharmaceutical Sciences, UIC College of Pharmacy at Rockford, Rockford, IL 61107, USA.
Aging (Albany NY). 2017 Jan 5;9(1):68-97. doi: 10.18632/aging.101114.
A progressive loss of genome maintenance has been implicated as both a cause and consequence of aging. Here we present evidence supporting the hypothesis that an age-associated decay in genome maintenance promotes aging in (yeast) due to an inability to sense or repair DNA damage by topoisomerase 2 (yTop2). We describe the characterization of LS1, identified in a high throughput screen for small molecules that shorten the replicative lifespan of yeast. LS1 accelerates aging without affecting proliferative growth or viability. Genetic and biochemical criteria reveal LS1 to be a weak Top2 poison. Top2 poisons induce the accumulation of covalent Top2-linked DNA double strand breaks that, if left unrepaired, lead to genome instability and death. LS1 is toxic to cells deficient in homologous recombination, suggesting that the damage it induces is normally mitigated by genome maintenance systems. The essential roles of yTop2 in proliferating cells may come with a fitness trade-off in older cells that are less able to sense or repair yTop2-mediated DNA damage. Consistent with this idea, cells live longer when yTop2 expression levels are reduced. These results identify intrinsic yTop2-mediated DNA damage as potentially manageable cause of aging.
基因组维持功能的逐渐丧失被认为是衰老的原因和结果。在此，我们提供证据支持以下假说：由于无法感知或修复拓扑异构酶2（yTop2）造成的DNA损伤，基因组维持功能随年龄增长的衰退会促进酵母衰老。我们描述了LS1的特征，它是在一项高通量筛选中发现的能缩短酵母复制寿命的小分子。LS1加速衰老，但不影响增殖生长或活力。遗传学和生物化学标准表明LS1是一种弱拓扑异构酶2毒物。拓扑异构酶2毒物会诱导共价连接拓扑异构酶2的DNA双链断裂的积累，如果不修复，会导致基因组不稳定和死亡。LS1对缺乏同源重组的细胞有毒性，这表明它诱导的损伤通常由基因组维持系统减轻。yTop2在增殖细胞中的重要作用可能在衰老细胞中伴随着适应性权衡，因为衰老细胞感知或修复yTop2介导的DNA损伤的能力较弱。与此观点一致的是，当yTop2表达水平降低时，细胞寿命会延长。这些结果表明，yTop2介导的内在DNA损伤可能是衰老的一个可控原因。
