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首页> 外文期刊>Cellular Signalling >Inner nuclear membrane protein Lem2 facilitates Rad3-mediated checkpoint signaling under replication stress induced by nucleotide depletion in fission yeast
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Inner nuclear membrane protein Lem2 facilitates Rad3-mediated checkpoint signaling under replication stress induced by nucleotide depletion in fission yeast

机译：内核膜蛋白Lem2在裂变酵母中核苷酸耗竭诱导的复制胁迫下促进Rad3介导的检查点信号转导

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摘要

DNA replication checkpoint is a highly conserved cellular signaling pathway critical for maintaining genome integrity in eukaryotes. It is activated when DNA replication is perturbed. In Schizosaccharomyces pombe, perturbed replication forks activate the sensor kinase Rad3 (ATR/Mec1), which works cooperatively with mediator Mrc1 and the 9-1-1 checkpoint clamp to phosphorylate the effector kinase Cds1 (CHK2/Rad53). Phosphorylation of Cds1 promotes autoactivation of the kinase. Activated Cds1 diffuses away from the forks and stimulates most of the checkpoint responses under replication stress. Although this signaling pathway has been well understood in fission yeast, how the signaling is initiated and thus regulated remains incompletely understood. Previous studies have shown that deletion of lem(2+) sensitizes cells to the inhibitor of ribonucleotide reductase, hydroxyurea. However, the underlying mechanism is still not well understood. This study shows that in the presence of hydroxyurea, Lem2 facilitates Rad3-mediated checkpoint signaling for Cds1 activation. Without Lem2, all known Rad3-dependent phosphorylations critical for replication checkpoint signaling are seriously compromised, which likely causes the aberrant mitosis and drug sensitivity observed in this mutant. Interestingly, the mutant is not very sensitive to DNA damage and the DNA damage checkpoint remains largely intact, suggesting that the main function of Lem2 is to facilitate checkpoint signaling in response to replication stress. Since Lem2 is an inner nuclear membrane protein, these results also suggest that the replication checkpoint may be spatially regulated inside the nucleus, a previously unknown mechanism. (C) 2015 Elsevier Inc. All rights reserved.
机译：DNA复制检查点是高度保守的细胞信号通路，对于维持真核生物的基因组完整性至关重要。 DNA复制受到干扰时，它会被激活。在粟酒裂殖酵母中，受干扰的复制叉激活了传感器激酶Rad3（ATR / Mec1），后者与介体Mrc1和9-1-1检查点钳位协同工作，以磷酸化效应激酶Cds1（CHK2 / Rad53）。 Cds1的磷酸化促进激酶的自激活。激活的Cds1从叉中扩散出来，并在复制压力下刺激大多数检查点响应。尽管在裂殖酵母中已经很好地理解了该信号转导途径，但是仍未完全理解如何启动信号转导以及如何调节信号转导。先前的研究表明，lem（2+）的删除会使细胞对核糖核苷酸还原酶羟基脲的抑制剂敏感。但是，其底层机制仍未得到很好的理解。这项研究表明，在羟基脲的存在下，Lem2促进Rad3介导的Cds1激活的检查点信号传导。没有Lem2，所有已知的对复制检查点信号至关重要的依赖Rad3的磷酸化都会受到严重损害，这很可能导致该突变体中观察到异常的有丝分裂和药物敏感性。有趣的是，该突变体对DNA损伤不是很敏感，并且DNA损伤检查点仍保持完整，这表明Lem2的主要功能是促进对复制压力的检查点信号传导。由于Lem2是内核膜蛋白，因此这些结果还表明复制检查点可能在核内在空间上受到调节，这是以前未知的机制。 （C）2015 Elsevier Inc.保留所有权利。

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