小柯机器人

美国斯坦福大学Karlene A. Cimprich研究组发现，R环衍生的细胞质RNA–DNA杂交激活免疫反应。相关论文于2022年12月21日在线发表在《自然》杂志上。

研究人员在细胞质中发现了一个新的RNA-DNA杂交体群体，它是R环的加工产物。当通过耗竭RNA-DNA螺旋酶SETX或乳腺癌基因BRCA1来扰乱核R环时，研究人员观察到XPG和XPF依赖的细胞质杂交体形成。研究人员将它们的来源确定为具有特定核苷酸特征的稳定、重叠的核内杂交体亚群。细胞质杂交体与模式识别受体cGAS和TLR3结合，激活IRF3并诱导细胞凋亡。在共济失调眼球运动障碍2型患者的SETX突变细胞和BRCA1突变的癌细胞中也观察到切除的杂交体和R环诱导的先天免疫反应。这些发现确定了RNA-DNA杂交体是免疫原性物种，在R环处理后异常地积累在细胞质中，从而将R环的积累与细胞死亡通过先天免疫反应联系起来。异常的R环处理和随后的先天免疫激活可能导致许多疾病，如神经变性和癌症。

据悉，R环是含有RNA-DNA杂交的核酸，具有重要的细胞作用。R环动态失调可导致DNA损伤和基因组不稳定，这与XPG等内切酶的作用有关。然而，这种处理的机制和细胞后果仍不清楚。

附：英文原文

Title: R-loop-derived cytoplasmic RNA–DNA hybrids activate an immune response

Author: Crossley, Magdalena P., Song, Chenlin, Bocek, Michael J., Choi, Jun-Hyuk, Kousorous, Joseph, Sathirachinda, Ataya, Lin, Cindy, Brickner, Joshua R., Bai, Gongshi, Lans, Hannes, Vermeulen, Wim, Abu-Remaileh, Monther, Cimprich, Karlene A.

Issue&Volume: 2022-12-21

Abstract: R-loops are RNA–DNA-hybrid-containing nucleic acids with important cellular roles. Deregulation of R-loop dynamics can lead to DNA damage and genome instability1, which has been linked to the action of endonucleases such as XPG2,3,4. However, the mechanisms and cellular consequences of such processing have remained unclear. Here we identify a new population of RNA–DNA hybrids in the cytoplasm that are R-loop-processing products. When nuclear R-loops were perturbed by depleting the RNA–DNA helicase senataxin (SETX) or the breast cancer gene BRCA1 (refs. 5,6,7), we observed XPG- and XPF-dependent cytoplasmic hybrid formation. We identify their source as a subset of stable, overlapping nuclear hybrids with a specific nucleotide signature. Cytoplasmic hybrids bind to the pattern recognition receptors cGAS and TLR3 (ref. 8), activating IRF3 and inducing apoptosis. Excised hybrids and an R-loop-induced innate immune response were also observed in SETX-mutated cells from patients with ataxia oculomotor apraxia type 2 (ref. 9) and in BRCA1-mutated cancer cells10. These findings establish RNA–DNA hybrids as immunogenic species that aberrantly accumulate in the cytoplasm after R-loop processing, linking R-loop accumulation to cell death through the innate immune response. Aberrant R-loop processing and subsequent innate immune activation may contribute to many diseases, such as neurodegeneration and cancer.

DOI: 10.1038/s41586-022-05545-9

Source: https://www.nature.com/articles/s41586-022-05545-9

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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