MRC Toxicology Unit, University of Cambridge, Cambridge CB21QR, UK.
MRC Toxicology Unit, University of Cambridge, Cambridge CB21QR, UK.
Mol Cell. 2024 Feb 15;84(4):687-701.e7. doi: 10.1016/j.molcel.2024.01.001. Epub 2024 Jan 23.
Molecular chaperones are critical for protein homeostasis and are implicated in several human pathologies such as neurodegeneration and cancer. While the binding of chaperones to nascent and misfolded proteins has been studied in great detail, the direct interaction between chaperones and RNA has not been systematically investigated. Here, we provide the evidence for widespread interaction between chaperones and RNA in human cells. We show that the major chaperone heat shock protein 70 (HSP70) binds to non-coding RNA transcribed by RNA polymerase III (RNA Pol III) such as tRNA and 5S rRNA. Global chromatin profiling revealed that HSP70 binds genomic sites of transcription by RNA Pol III. Detailed biochemical analyses showed that HSP70 alleviates the inhibitory effect of cognate tRNA transcript on tRNA gene transcription. Thus, our study uncovers an unexpected role of HSP70-RNA interaction in the biogenesis of a specific class of non-coding RNA with wider implications in cancer therapeutics.
分子伴侣对于蛋白质的内环境稳定至关重要，并与多种人类疾病相关，如神经退行性疾病和癌症。虽然伴侣蛋白与新生和错误折叠的蛋白质的结合已经被深入研究，但伴侣蛋白与 RNA 之间的直接相互作用尚未被系统地研究。在这里，我们提供了证据证明伴侣蛋白与人类细胞中的 RNA 之间存在广泛的相互作用。我们表明，主要的伴侣蛋白热休克蛋白 70（HSP70）与由 RNA 聚合酶 III（RNA Pol III）转录的非编码 RNA 结合，如 tRNA 和 5S rRNA。全基因组染色质分析显示，HSP70 结合 RNA Pol III 转录的基因组位点。详细的生化分析表明，HSP70 减轻了同源 tRNA 转录本对 tRNA 基因转录的抑制作用。因此，我们的研究揭示了 HSP70-RNA 相互作用在一类特定的非编码 RNA 生物发生中的意外作用，这对癌症治疗具有更广泛的意义。
