Role for perinuclear chromosome tethering in maintenance of genome stability.
Role for perinuclear chromosome tethering in maintenance of genome stability.
复制标题
核周染色体束缚在维持基因组稳定性中的作用。
DOI：
10.1038/nature07460
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发表时间：
2008-12-04
期刊：
影响因子：
64.8
通讯作者：
Moazed, Danesh
中科院分区：
文献类型：
--
作者：
Mekhail, Karim;Seebacher, Jan;Gygi, Steven P.;Moazed, Danesh
在某些生物体中，构成基因组一半的重复DNA序列经常发生同源重组。这可能由于DNA的获得或丢失而引起基因组的不稳定。DNA组装成沉默的染色质通常被认为是一种通过限制进入重组机制来确保重复稳定性的机制。与这一观点一致的是，在出芽酵母中，高度重复核糖体DNA （rDNA）序列的稳定性需要含有sir2的染色质沉默复合体，该复合体还可以抑制插入重复序列中的外来启动子和转座子的转录，这一过程称为rDNA沉默。在这里，我们描述了一个蛋白质网络，通过rDNA相关的沉默蛋白和两种核膜（INM）蛋白之间的相互作用来稳定出芽酵母的rDNA重复序列。无论是INM蛋白还是沉默蛋白的缺失都会减少核周rDNA定位，破坏核仁-核质边界，诱导重组灶的形成，并使重复序列不稳定。此外，在缺乏rDNA相关沉默蛋白的细胞中，将rDNA重复序列人工靶向INM可以抑制细胞的不稳定性，而rDNA相关沉默蛋白通常是外周拴链所必需的。此外，与Sir2及其相关核仁因子相比，INM蛋白不需要rDNA沉默，这表明Sir2依赖性沉默不足以抑制rDNA位点内的重组。这些发现证明了INM蛋白在核周围染色体定位中的作用，并表明rDNA重复序列的稳定性需要与核周围的连接。这里研究的INM蛋白是保守的，并且与后生动物的染色体组织有关。因此，我们的研究结果揭示了一种古老的机制，在这种机制中，INM和染色体蛋白之间的相互作用确保了基因组的稳定性。
Repetitive DNA sequences, which constitute half the genome in some organisms, often undergo homologous recombination. This can instigate genomic instability due to gain or loss of DNA. Assembly of DNA into silent chromatin is generally thought to serve as a mechanism ensuring repeat stability by limiting access to the recombination machinery. Consistent with this notion, in the budding yeast Saccharomyces cerevisiae, stability of the highly repetitive ribosomal DNA (rDNA) sequences requires a Sir2-containing chromatin silencing complex that also inhibits transcription from foreign promoters and transposons inserted within the repeats by a process called rDNA silencing. Here, we describe a protein network that stabilizes rDNA repeats of budding yeast via interactions between rDNA-associated silencing proteins and two inner nuclear membrane (INM) proteins. Deletion of either the INM or silencing proteins reduces perinuclear rDNA positioning, disrupts the nucleolus-nucleoplasm boundary, induces the formation of recombination foci, and destabilizes the repeats. In addition, artificial targeting of rDNA repeats to the INM suppresses the instability observed in cells lacking an rDNA-associated silencing protein typically required for peripheral tethering of the repeats. Moreover, in contrast to Sir2 and its associated nucleolar factors, the INM proteins are not required for rDNA silencing, indicating that Sir2-dependent silencing is not sufficient to inhibit recombination within the rDNA locus. These findings demonstrate a role for INM proteins in perinuclear chromosome localization and show that tethering to the nuclear periphery is required for rDNA repeat stability. The INM proteins studied here are conserved and have been implicated in chromosome organization in metazoans. Our results therefore reveal an ancient mechanism in which interactions between INM and chromosomal proteins ensure genome stability.
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影响因子：
10.5
作者：
Huang, Julie;Brito, Ilana L.;Moazed, Danesh
通讯作者：
Moazed, Danesh
影响因子：
64.8
作者：
Reddy, K. L.;Zullo, J. M.;Singh, H.
通讯作者：
Singh, H.
DOI：
10.1101/sqb.2001.66.555
发表时间：
2001-01-01
期刊：
COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY
影响因子：
--
作者：
Nomura, M
通讯作者：
Nomura, M
影响因子：
30.8
作者：
Hellemans, J;Preobrazhenska, O;Mortier, GR
通讯作者：
Mortier, GR
影响因子：
64.5
作者：
KEIL, RL;ROEDER, GS
通讯作者：
ROEDER, GS