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A hypoxia-responsive tRNA-derived small RNA confers renal protection via RNA autophagy

ABSTRACT: Emerging studies have revealed diverse cellular functions of tRNA-derived small RNAs (tsRNAs, or tDRs). Here, we show that a hypoxia-induced tDR, derived from the 3’ end of tRNA-Asp-GTC (tRNA-Asp-GTC-3’tDR), activates, while its inhibition blocks autophagic flux in kidney cells. Functional gain/loss-of-function studies in murine kidney disease models demonstrate a significant reno-protective function of tRNA-Asp-GTC-3’tDR. Mechanistically, tRNA-Asp-GTC-3’tDR assembles stable G-quadruplex structures and sequesters pseudouridine synthase PUS7, preventing catalytic pseudouridylation of histone mRNAs. The resulting pseudouridylation deficiency directs histone mRNAs to the autophagosome-lysosome pathway, triggering RNA autophagy. We confirm this tDR-induced RNA autophagy pathway in murine and human kidney diseases. Together, our findings identify a novel role for tRNA-Asp-GTC-3’tDR in regulating RNA autophagy in kidney cells to maintain homeostasis and protect against kidney injury.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289124 | GEO | 2025/02/12

REPOSITORIES: GEO

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Project description:Background: Resistance to trastuzumab remains a common challenge to HER-2 positive breast cancer. Up until now, the underlying mechanism of trastuzumab resistance is still unclear. tRNA-derived small non-coding RNAs (tDRs), a new class of small non-coding RNA (sncRNAs), have been observed to play an important role in cancer progression. However, the relationship between tDRs and trastuzumab resistance is still unknown. Methods: We detected the levels of tDRs expression in normal breast epithelial cell lines, trastuzumab-sensitive and -resistant breast cancer cell lines using high-throughput sequencing. qRT-PCR was conducted to validate the differentially expressed tDRs in serums from trastuzumab-sensitive and -resistant patients. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the power of specific tDRs. Progression-free survival (PFS) was analyzed using Cox-regression. Furthermore, Gene Ontology (GO) and pathway analyses indicated the potential mechanism underlying tDR-mediated trastuzumab resistance. Results: Our sequence results showed that tDRs were differentially expressed in the HBL-100, SKBR3, and JIMT-1 cell lines. tDR-1960 and tDR-1969 were found significantly upregulated in trastuzumab-resistant patients compared to sensitive individuals, and the ROC analysis showed that tDR-1960 and tDR-1969 were correlated with trastuzumab resistance. In a multivariate analysis, higher levels of tDR-1960 and tDR-1969 expression were associated with signiﬁcantly shorter PFS in patients with metastatic HER-2 positive breast cancer. Additionally, the GO analysis indicated that tDR-1960 and tDR-1969 were mainly involved in the cellular response to drug, which may partially explain the molecular mechanism underlying trastuzumab resistance in HER-2 positive breast cancer. Conclusion: we comprehensively analyzed tDRs in trastuzumab-sensitive and -resistant breast cancer. Our results suggest that tDR-1960 and tDR-1969 play important roles in trastuzumab resistance. Patients with high levels of tDR-1960 and tDR-1969 expression benefitted less from trastuzumab-based therapy than those that express lower-levels of these tDRs. tDR-1960 and tDR-1969 may be potential biomarkers and intervention targets in the clinical treatment of trastuzumab-resistant breast cancer.

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A hypoxia-responsive tRNA-derived small RNA confers renal protection via RNA autophagy

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