Deregulated Expression of Mammalian lncRNA through Loss of SPT6 Induces R-Loop Formation, Replication Stress, and Cellular Senescence.
Deregulated Expression of Mammalian lncRNA through Loss of SPT6 Induces R-Loop Formation, Replication Stress, and Cellular Senescence.
复制标题
DOI：
10.1016/j.molcel.2018.10.011
复制
发表时间：
2018-12-20
期刊：
影响因子：
16
通讯作者：
Proudfoot NJ
中科院分区：
文献类型：
--
作者：
Nojima T;Tellier M;Foxwell J;Ribeiro de Almeida C;Tan-Wong SM;Dhir S;Dujardin G;Dhir A;Murphy S;Proudfoot NJ
哺乳动物基因组中大量缺乏蛋白质编码功能的片段仍然被转录成长的非编码RNA。虽然这些lncRNA通常是短寿命的，长度受限的，和非多聚腺苷酸化的，但它们的表达如何与蛋白质编码基因区分仍然是个谜。令人惊讶的是，普遍存在的Pol-II相关转录延伸因子SPT 6的耗尽促进了H3 K36 me 3组蛋白标记从活性蛋白编码到lncRNA基因的重新分布，这与lncRNA转录增加相关。SPT 6敲低还损害整合子复合物向染色质的募集，这导致lncRNA基因的转录终止缺陷。这导致形成延伸的多腺苷酸化的lncRNA，其既受染色质限制又形成与DNA损伤相关的RNA：DNA杂合体（R环）水平增加。此外，这些失调的lncRNA与DNA复制起点重叠，导致局部DNA复制应激和细胞衰老表型。总的来说，我们的结果强调了限制lncRNA表达的重要性。SPT 6促进H3 K36 me 3在蛋白质编码基因上的选择性分布SPT 6缺失导致易于形成R环的延伸lncRNA的形成解除调节的Pol II与lncRNA基因上的DNA复制体碰撞Pol II与DNA复制体之间的碰撞导致细胞衰老Nojima和同事证明了人类SPT 6蛋白的缺失提高了非编码转录的水平并扰乱了其终止。去调节的非编码转录增加了R环的形成，随之而来的是DNA损伤、转录-复制碰撞和细胞衰老。这意味着非编码转录受到限制，以避免增殖细胞中的这种冲突。
Extensive tracts of the mammalian genome that lack protein-coding function are still transcribed into long noncoding RNA. While these lncRNAs are generally short lived, length restricted, and non-polyadenylated, how their expression is distinguished from protein-coding genes remains enigmatic. Surprisingly, depletion of the ubiquitous Pol-II-associated transcription elongation factor SPT6 promotes a redistribution of H3K36me3 histone marks from active protein coding to lncRNA genes, which correlates with increased lncRNA transcription. SPT6 knockdown also impairs the recruitment of the Integrator complex to chromatin, which results in a transcriptional termination defect for lncRNA genes. This leads to the formation of extended, polyadenylated lncRNAs that are both chromatin restricted and form increased levels of RNA:DNA hybrid (R-loops) that are associated with DNA damage. Additionally, these deregulated lncRNAs overlap with DNA replication origins leading to localized DNA replication stress and a cellular senescence phenotype. Overall, our results underline the importance of restricting lncRNA expression. SPT6 promotes the selective distribution of H3K36me3 over protein-coding genes SPT6 loss leads to formation of extended lncRNAs that are prone to R-loop formation Deregulated Pol II collides with DNA replisomes on lncRNA genes Collision between Pol II and DNA replisome leads to cellular senescence Nojima and colleagues demonstrate that loss of human SPT6 protein elevates levels of noncoding transcription and perturbs its termination. The deregulated noncoding transcription increases R-loop formation with consequent DNA damage, transcription-replication collision, and cellular senescence. This implies that noncoding transcription is restricted to avoid such conflicts in proliferating cells.
登录
查看更多内容
影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Lai F;Gardini A;Zhang A;Shiekhattar R
通讯作者：
Shiekhattar R
影响因子：
64.5
作者：
Li, XL;Manley, JL
通讯作者：
Manley, JL
影响因子：
10.5
作者：
Henriques T;Scruggs BS;Inouye MO;Muse GW;Williams LH;Burkholder AB;Lavender CA;Fargo DC;Adelman K
通讯作者：
Adelman K