Multiple signaling kinases target Mrc1 to prevent genomic instability triggered by transcription-replication conflicts
Multiple signaling kinases target Mrc1 to prevent genomic instability triggered by transcription-replication conflicts
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DOI：
10.1038/s41467-017-02756-x
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发表时间：
2018-01-25
影响因子：
16.6
通讯作者：
Posas, Francesc
中科院分区：
文献类型：
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作者：
Duch, Alba;Canal, Berta;Posas, Francesc
复制和转录机制之间的冲突是基因组不稳定的主要来源，细胞已经进化出防止这种冲突的策略。然而，关于细胞在复制过程中如何应对转录的突然增加，人们知之甚少。在这里，我们报告了Mrc1介导的S期转录爆发时保护基因组完整性的一般机制的存在。在S期应激诱导的基因表达过程中，Mrc1的n端磷酸化阻断了复制，阻止了转录相关重组（TAR）和基因组不稳定性。无偏倚的kinome筛选鉴定了几种激酶，这些激酶在不同的环境胁迫下磷酸化Mrc1的N端。Mrc1的功能并不局限于环境因素，当基因组不稳定或生长缓慢等低适应度状态触发非预定转录时，也需要Mrc1的功能。我们的数据表明，Mrc1整合了多个信号，从而定义了一种通用的保护机制，以保护转录爆发时的基因组完整性。
Conflicts between replication and transcription machineries represent a major source of genomic instability and cells have evolved strategies to prevent such conflicts. However, little is known regarding how cells cope with sudden increases of transcription while replicating. Here, we report the existence of a general mechanism for the protection of genomic integrity upon transcriptional outbursts in S phase that is mediated by Mrc1. The N-terminal phosphorylation of Mrc1 blocked replication and prevented transcription-associated recombination (TAR) and genomic instability during stress-induced gene expression in S phase. An unbiased kinome screening identified several kinases that phosphorylate Mrc1 at the N terminus upon different environmental stresses. Mrc1 function was not restricted to environmental cues but was also required when unscheduled transcription was triggered by low fitness states such as genomic instability or slow growth. Our data indicate that Mrc1 integrates multiple signals, thereby defining a general safeguard mechanism to protect genomic integrity upon transcriptional outbursts.