R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements.
R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements.
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R-loops和年龄衰老的裂变酵母细胞的调节变化驱动基因组重排的非随机模式。
DOI：
10.1371/journal.pgen.1009784
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发表时间：
2021-08
期刊：
影响因子：
4.5
通讯作者：
Bähler J
中科院分区：
文献类型：
--
作者：
Ellis DA;Reyes-Martín F;Rodríguez-López M;Cotobal C;Sun XM;Saintain Q;Jeffares DC;Marguerat S;Tallada VA;Bähler J
DNA双链断裂的异常修复可以重组远处的染色体断裂点。染色体重排损害基因组功能，是衰老的标志。在非分裂细胞群体中检测重排具有挑战性，因为它们反映了个体罕见的异质事件。因此，在非分裂细胞中从头重排的基因组分布及其在衰老过程中的动力学特征仍然很差。衰老过程中基因组不稳定性的研究主要集中在线粒体DNA、小的遗传变异或增殖细胞上。为了表征非分裂细胞中细胞老化过程中的基因组重排，我们询问了一个单一的诊断措施，DNA断点连接，使用裂殖酵母作为模型系统。随着年龄的增长而积累的异常DNA连接与微同源序列和R环相关。年龄相关断裂点形成的全球热点在端粒基因附近很明显，并与基因组中其他地方的远程断裂点（包括线粒体染色体）相关。在全球热点的断点连接的形成受到抑制的Sir 2组蛋白脱乙酰酶，并可能引发的年龄依赖性去抑制染色质沉默。基因组不稳定性的一个意想不到的机制可能会导致更多的局部热点：与年龄相关的RNA结合蛋白减少，触发靶位点的R环。这一结果表明，转录或复制以外的生物过程可以驱动基因组重排。值得注意的是，我们检测到了在人类旧脑细胞中积累的基因组重排的类似特征。这些发现提供了对非分裂细胞中基因组重排的独特模式和可能机制的见解，这可以通过基因调控蛋白中与衰老相关的变化来促进。DNA断裂后，染色体重排连接非相邻的DNA序列可能会严重影响基因功能，进化和衰老。这样的染色体重排很难在序列数据中发现，即使它们是普遍存在的，因为它们是单独罕见的，反映了不同的事件。在这里，我们建立灵敏的DNA序列分析，并确定普遍的重排，特别是在酵母细胞老化过程中积累。这些重排的特征是断裂附近的短重复DNA序列，优先发生在染色体的某些位置（例如，在它们的末端附近），并且可以连接源自不同染色体的序列。我们的结果表明，DNA-RNA的相互作用，由年龄相关的RNA结合蛋白的抑制触发，可以导致一些染色体重排的非随机模式。我们的分析表明，类似的染色体重排模式在老年人的脑细胞中积累，这提高了衰老细胞中发生的这种DNA变化从酵母到人类都是保守的可能性。
Aberrant repair of DNA double-strand breaks can recombine distant chromosomal breakpoints. Chromosomal rearrangements compromise genome function and are a hallmark of ageing. Rearrangements are challenging to detect in non-dividing cell populations, because they reflect individually rare, heterogeneous events. The genomic distribution of de novo rearrangements in non-dividing cells, and their dynamics during ageing, remain therefore poorly characterized. Studies of genomic instability during ageing have focussed on mitochondrial DNA, small genetic variants, or proliferating cells. To characterize genome rearrangements during cellular ageing in non-dividing cells, we interrogated a single diagnostic measure, DNA breakpoint junctions, using Schizosaccharomyces pombe as a model system. Aberrant DNA junctions that accumulated with age were associated with microhomology sequences and R-loops. Global hotspots for age-associated breakpoint formation were evident near telomeric genes and linked to remote breakpoints elsewhere in the genome, including the mitochondrial chromosome. Formation of breakpoint junctions at global hotspots was inhibited by the Sir2 histone deacetylase and might be triggered by an age-dependent de-repression of chromatin silencing. An unexpected mechanism of genomic instability may cause more local hotspots: age-associated reduction in an RNA-binding protein triggering R-loops at target loci. This result suggests that biological processes other than transcription or replication can drive genome rearrangements. Notably, we detected similar signatures of genome rearrangements that accumulated in old brain cells of humans. These findings provide insights into the unique patterns and possible mechanisms of genome rearrangements in non-dividing cells, which can be promoted by ageing-related changes in gene-regulatory proteins. DNA breaks followed by chromosomal rearrangements that join non-neighboring DNA sequences may critically affect gene function, evolution, and ageing. Such chromosomal rearrangements are difficult to spot in sequence data even if they are widespread, because they are individually rare and reflect diverse events. Here we establish sensitive analyses of DNA sequences and identify prevalent rearrangements that specifically accumulate during ageing in yeast cells. These rearrangements feature short repeated DNA sequences near the breaks, preferentially occur in certain locations of the chromosomes (e.g., near their ends), and can link sequences originating from different chromosomes. We show results indicating that DNA-RNA interactions, triggered by the ageing-associated suppression of an RNA-binding protein, can cause the non-random patterns of some chromosomal rearrangements. Our analyses suggest that similar patterns of chromosomal rearrangements accumulate in brain cells in older humans, raising the possibility that such DNA changes occurring in ageing cells are conserved from yeast to human.
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Biopython：用于计算分子生物学和生物信息学的免费 Python 工具。
DOI：
10.1093/bioinformatics/btp163
发表时间：
2009-06-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
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影响因子：
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作者：
Ellis DA;Mustonen V;Rodríguez-López M;Rallis C;Malecki M;Jeffares DC;Bähler J
通讯作者：
Bähler J
DOI：
10.1261/rna.065524.118
发表时间：
2018-09
期刊：
RNA (New York, N.Y.)
影响因子：
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影响因子：
10.5
作者：
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