上调应激细胞中基因转录会导致转录和修复机制之间的冲突,来自西班牙法普拉大学的科学家发现一种压力活化蛋白激酶Hog1可以协调酵母中这两种过程。

-2013年1月3日《自然》


中文翻译


【题目】依赖SAPK的复制和转录的协同控制保护基因组完整性

【译文】胞外信号环境变化时,导致细胞的基因表达发生显著变化。复制期间处理高水平转录对于阻止转录和复制通路间冲突以及避免重组事件发生至关重要。 应答渗透胁迫时,数百个基因被压力激活蛋白激酶(SAPK)Hog1快速诱导,甚至在S期。本研究表明啤酒酵母中单信号分子Hog1协调渗透压条件下的复制和转录。Hog1与Mrc1互作并磷酸化Mrc1。Mrc1是复制复合物的组分。DNA损伤条件下,磷酸化发生在Mec1靶向的不同位点。Mrc1依赖Hog1的磷酸化通过阻断Cdc45载入延缓了早期和晚期起始启动,同时减缓了复制复合物进展。 Hog1对Mrc1的调控完全与Mec1和Rad53无关。胁迫条件下,携带MRC1(mrc13A)非磷酸化等位基因的细胞不会延缓复制,并且转录相关重组、基因组不稳定和Rad52显著增加。相反,mrc13A诱导Rad53并在羟脲或甲基安乃近存在时生存。因此,Hog1和Mrc1界定了独立于DNA损伤检查点的S期检查点,DNA损伤检查点允许真核细胞阻止DNA复制和转录间的冲突,当两种现象短暂一致时这种冲突会导致基因组不稳定。

英文原稿


[Title]: Coordinated control of replication and transcription by a SAPK protects genomic integrity

[Authors]:Alba Duch,1 Irene Felipe-Abrio,2 Sonia Barroso,2 Gilad Yaakov,1 María García-Rubio,2 Andrés Aguilera,2 Eulàlia de Nadal1 & Francesc Posas1

[Abstract]Upon environmental changes or extracellular signals, cells are subjected to marked changes in gene expression. Dealing with high levels of transcription during replication is critical to prevent collisions between the transcription and replication pathways and avoid recombination events. In response to osmostress, hundreds of stress-responsive genes are rapidly induced by the stress-activated protein kinase (SAPK) Hog1, even during S phase. Here we show in Saccharomyces cerevisae that a single signalling molecule, Hog1, coordinates both replication and transcription upon osmostress. Hog1 interacts with and phosphorylates Mrc1, a component of the replication complex. Phosphorylation occurs at different sites to those targeted by Mec1 upon DNA damage. Mrc1 phosphorylation by Hog1 delays early and late origin firing by preventing Cdc45 loading, as well as slowing down replication-complex progression. Regulation of Mrc1 by Hog1 is completely independent of Mec1 and Rad53. Cells carrying a non-phosphorylatable allele of MRC1 (mrc13A) do not delay replication upon stress and show a marked increase in transcription-associated recombination, genomic instability and Rad52 foci. In contrast, mrc13A induces Rad53 and survival in the presence of hydroxyurea or methyl methanesulphonate. Therefore, Hog1 and Mrc1 define a novel S-phase checkpoint independent of the DNA-damage checkpoint that permits eukaryotic cells to prevent conflicts between DNA replication and transcription, which would otherwise lead to genomic instability when both phenomena are temporally coincident.

原文地址

http://www.nature.com/nature/journal/v493/n7430/full/nature11675.html

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