Adaptive responses to stress are essential for cell and organismal survival. In metazoans, little is known about the impact of environmental stress on RNA homeostasis. By studying the regulation of a cadmium-induced gene named numr-1 in Caenorhabditis elegans, we discovered that disruption of RNA processing acts as a signal for environmental stress. We find that NUMR-1 contains motifs common to RNA splicing factors and influences RNA splicing in vivo. A genome-wide screen reveals that numr-1 is strongly and specifically induced by silencing of genes that function in basal RNA metabolism including subunits of the metazoan integrator complex. Human integrator processes snRNAs for functioning with splicing factors, and we find that silencing of C. elegans integrator subunits disrupts snRNA processing, causes aberrant pre-mRNA splicing, and induces the heat shock response. Cadmium, which also strongly induces numr-1, has similar effects on RNA and the heat shock response. Lastly, we find that heat shock factor-1 is required for full numr-1 induction by cadmium. Our results are consistent with a model in which disruption of integrator processing of RNA acts as a molecular damage signal initiating an adaptive stress response mediated by heat shock factor-1. When numr-1 is induced via this pathway in C. elegans, its function in RNA metabolism may allow it to mitigate further damage and thereby promote tolerance to cadmium.

中文翻译：

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镉和整合子复合物破坏引发的RNA处理错误是环境压力的信号

对压力的适应性反应对于细胞和机体的生存至关重要。在后生动物中，关于环境压力对RNA动态平衡的影响知之甚少。通过研究秀丽隐杆线虫中镉诱导的名为numr-1的基因的调控，我们发现RNA加工的破坏是环境胁迫的信号。我们发现NUMR-1包含RNA剪接因子共有的基序，并影响体内RNA剪接。全基因组筛选显示numr-1是由沉默在基础RNA代谢中起作用的基因（包括后生动物整合子的亚基）沉默而强烈诱导的。人类整合者会处理具有剪接因子功能的snRNA，而我们发现线虫整合子亚基的沉默会破坏snRNA的加工过程，导致异常的pre-mRNA剪接，并引起热冲击响应。也会强烈诱导numr-1的镉对RNA和热休克反应具有相似的作用。最后，我们发现热激因子1是镉诱导全部numr-1所必需的。我们的结果与一个模型一致，在该模型中，RNA整合子加工的破坏起分子损伤信号的作用，引发了由热激因子-1介导的适应性应激反应。当秀丽隐杆线虫通过该途径诱导numr-1时，其在RNA代谢中的功能可能使其减轻进一步的损害，从而提高对镉的耐受性。我们的结果与一个模型一致，在该模型中，RNA整合子加工的破坏起分子损伤信号的作用，引发了由热激因子-1介导的适应性应激反应。当秀丽隐杆线虫通过该途径诱导numr-1时，其在RNA代谢中的功能可能使其减轻进一步的损害，从而提高对镉的耐受性。我们的结果与一个模型一致，在该模型中，RNA整合子加工的破坏起分子损伤信号的作用，引发了由热激因子-1介导的适应性应激反应。当秀丽隐杆线虫通过该途径诱导numr-1时，其在RNA代谢中的功能可能使其减轻进一步的损害，从而提高对镉的耐受性。