Rap1 relocalization contributes to the chromatin-mediated gene expression profile and pace of cell senescence
Rap1 relocalization contributes to the chromatin-mediated gene expression profile and pace of cell senescence
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DOI：
10.1101/gad.218776.113
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发表时间：
2013-06-15
影响因子：
10.5
通讯作者：
Johnson, F. Brad
中科院分区：
文献类型：
--
作者：
Platt, Jesse M.;Ryvkin, Paul;Johnson, F. Brad
细胞衰老伴随着染色质结构和基因表达的急剧变化。使用缺乏端粒酶的酿酒酵母突变体（tlc 1 Delta）来模拟衰老，我们发现，随着关键的端粒缩短，端粒结合蛋白Rap 1（阻遏物激活蛋白1）重新定位到数百个新靶基因的上游启动子区域。一组新的Rap 1衰老靶点（NRTS）在衰老时优先激活，Rap 1水平的实验操作表明，它直接有助于NRTS激活。NRTS的一个值得注意的子集包括核心组蛋白编码基因;我们发现Rap 1有助于它们的抑制，并且组蛋白水平在衰老时下降。Rap 1和组蛋白也显示出靶位点特异性拮抗作用，导致上调NRTS启动子的核小体占据减少。这种拮抗作用显然影响衰老的速率，因为Rap 1的低表达或核心组蛋白的过表达延迟衰老。Rap 1的重新定位并不是端粒结合位点丢失的简单结果，而是依赖于Mec 1检查点激酶。因此，Rap 1重新定位是一种新的机制，将端粒的DNA损伤反应（DDRs）与染色质和基因表达的整体变化联系起来，同时驱动衰老的步伐。
Cellular senescence is accompanied by dramatic changes in chromatin structure and gene expression. Using Saccharomyces cerevisiae mutants lacking telomerase (tlc1 Delta) to model senescence, we found that with critical telomere shortening, the telomere-binding protein Rap1 (repressor activator protein 1) relocalizes to the upstream promoter regions of hundreds of new target genes. The set of new Rap1 targets at senescence (NRTS) is preferentially activated at senescence, and experimental manipulations of Rap1 levels indicate that it contributes directly to NRTS activation. A notable subset of NRTS includes the core histone-encoding genes; we found that Rap1 contributes to their repression and that histone protein levels decline at senescence. Rap1 and histones also display a target site-specific antagonism that leads to diminished nucleosome occupancy at the promoters of up-regulated NRTS. This antagonism apparently impacts the rate of senescence because underexpression of Rap1 or overexpression of the core histones delays senescence. Rap1 relocalization is not a simple consequence of lost telomere-binding sites, but rather depends on the Mec1 checkpoint kinase. Rap1 relocalization is thus a novel mechanism connecting DNA damage responses (DDRs) at telomeres to global changes in chromatin and gene expression while driving the pace of senescence.