The long and short of rDNA and yeast replicative aging.
The long and short of rDNA and yeast replicative aging.
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DOI：
10.1073/pnas.2205124119
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发表时间：
2022-06-07
影响因子：
11.1
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中科院分区：
文献类型：
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芽殖酵母（Saccharomyces cerevisiae）是一种流行的用于研究衰老机制的单细胞真核模型，在几个保守的长寿因子的鉴定和表征中发挥了关键作用，包括典型的 NAD+ 依赖性组蛋白脱乙酰酶 Sir2，它可以沉默转录并维持 XII 号染色体上核糖体 DNA (rDNA) 串联阵列的稳定性（参考文献 1 进行了综述）。 Sir2 蛋白家族的其他成员（sirtuins）调节与无脊椎动物模型和哺乳动物衰老相关的众多细胞功能，从而使它们成为当前衰老研究的核心参与者 (2)。 rDNA 串联阵列是真核基因组中最不稳定的基因座之一，包含多达数百个 rRNA 基因，由核仁中的 RNA 聚合酶 I 转录以驱动核糖体生物发生。在酿酒酵母中，单个 rDNA 阵列特别不稳定，因为母细胞由于基因间间隔区内的 DNA 双链断裂 (DSB) 而复制老化。修复这些断裂可能导致母细胞中染色体外 rDNA 环 (ERC) 的切除和积累，最终导致其衰老 (3)。 Sir2 的沉默通常会抑制年轻细胞中的不当切除，但老年细胞中 Sir2 的自然耗竭会导致不稳定 (4)。 Hotz 等人 (5) 现在在 PNAS 中证明，ERC 和 Sir2 水平以及大多数菌株的复制老化的主要决定因素是 rDNA 串联阵列的实际长度（拷贝数）（图 1）。这对于解释酵母复制寿命（RLS）研究具有重要意义，并表明在后生动物衰老研究中应解决 rDNA 拷贝数问题。酿酒酵母的 RLS 定义为母细胞在失去活力之前分裂（芽）的次数。传统上，这个数字是通过在琼脂板表面手动显微解剖母细胞和子细胞来测量的，最近，Hotz 等人采用了自动跟踪数百个母细胞的高通量微流体装置(5)。 RLS 被认为是多细胞生物（例如干细胞）分裂细胞的衰老模型，其依赖于营养信号传导、翻译和 DNA 复制/修复等生长相关功能，所有这些都可能导致基因组随着年龄的增长而不稳定。因此，基因组不稳定性是从酵母到哺乳动物的衰老标志之一 (6)。 DSB 是一种严重的 DNA 损伤，如果不修复，会导致细胞死亡。 rDNA 阵列特别容易出现 DSB，因为通过高度转录的重复基因座进行 DNA 复制存在固有的困难，并且具有与其相关的不寻常结构，例如 R 环或 G 四链体 (7)。在复制压力期间，复制叉在此类障碍物上停滞可能会因叉崩溃而导致 DSB (8)。酿酒酵母 rDNA 还在基因间间隔区内包含一个主要复制叉块 (RFB) 位点，该位点由位点特异性 DNA 结合蛋白（称为
The budding yeast, Saccharomyces cerevisiae, is a popular single-cell eukaryotic model for studying mechanisms of aging, having played key roles in the identification and characterization of several conserved longevity factors, including the canonical NAD+-dependent histone deacetylase Sir2 that silences transcription and maintains stability of the ribosomal DNA (rDNA) tandem array on chromosome XII (reviewed in ref. 1). Other Sir2 protein family members, the sirtuins, regulate numerous cellular functions linked with the aging of invertebrate models and mammals, thus making them central players in current aging research (2). The rDNA tandem arrays are among the most unstable loci in eukaryotic genomes, comprising up to hundreds of rRNA genes transcribed by RNA polymerase I in the nucleolus to drive ribosome biogenesis. In S. cerevisiae, the single rDNA array is especially unstable, as mother cells replicatively age due to DNA double-strand breaks (DSBs) within the intergenic spacers. Repair of these breaks can result in the excision and accumulation of extrachromosomal rDNA circles (ERCs) in mother cells that ultimately contribute to their senescence (3). Silencing by Sir2 normally suppresses improper excision in young cells, but natural depletion of Sir2 in older cells causes instability (4). In PNAS, Hotz et al.(5) now demonstrate that a major determinant of ERC and Sir2 levels, and therefore replicative aging in most strains, is the actual length (copy number) of the rDNA tandem array (Fig. 1). This has important implications for the interpretation of yeast replicative lifespan (RLS) studies and signals that rDNA copy number should be addressed in metazoan aging studies. RLS of S. cerevisiae is defined as the number of times a mother cell divides (buds) before losing viability. This number is traditionally measured by manual microscopic dissection of mother and daughter cells on the surface of an agar plate, and, more recently, using high-throughput microfluidics devices that automatically track hundreds of mother cells, as carried out by Hotz et al.(5). RLS is considered an aging model for dividing cells of multicellular organisms, such as stem cells, which depend on growthrelated functions like nutrient signaling, translation, and DNA replication/repair, all of which can lead to genome instability with age.Accordingly, genomic instability is one of the hallmarks of aging conserved from yeast to mammals (6). DSBs are a severe form of DNA damage that result in cell death if left unrepaired. The rDNA array is especially prone to DSBs because of the inherent difficulty of DNA replication through a highly transcribed repetitive locus and the unusual structures associated with it, such as R-loops or G-quadruplexes (7). Replication fork stalling at such obstacles during replication stress can result in DSBs due to fork collapse (8). S. cerevisiae rDNA also harbors a major replication fork block (RFB) site within the intergenic spacer mediated by a site-specific DNA binding protein called
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
DOI：
10.1534/g3.116.030296
发表时间：
2016-09-08
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Kwan EX;Wang XS;Amemiya HM;Brewer BJ;Raghuraman MK
通讯作者：
Raghuraman MK
影响因子：
3.2
作者：
Wierman MB;Smith JS
通讯作者：
Smith JS
影响因子：
16
作者：
Defossez, PA;Prusty, R;Guarente, L
通讯作者：
Guarente, L
影响因子：
4.5
作者：
Lindstrom DL;Leverich CK;Henderson KA;Gottschling DE
通讯作者：
Gottschling DE