SNORD80-guided 2’-O-methylation stabilizes the lncRNA GAS5 to regulate cellular stress responses

The introns of the gene encoding the long noncoding RNA (lncRNA) GAS5 host up to 10 C/D box small nucleolar RNAs (snoRNAs). However, whether there is a regulatory and functional relationship between these snoRNAs and GAS5 is unknown. Here, we show that the expression of SNORD80, but not the other snoRNAs, parallels GAS5 expression and is regulated alongside GAS5 in response to cellular stress. The 2'-O-methylation at the A496 site, located within a segment of GAS5 complementing the conserved RNA-binding region on SNORD80, promotes GAS5 stability and consequent upregulation. This methylation requires SNORD80, as it is diminished by knockdown of SNORD80 and increased by SNORD80 overexpression, similar to the effects of manipulating the expression of fibrillarin, the methyltransferase of the box C/D small nucleolar ribonucleoprotein particle (snoRNP). The upregulation of SNORD80 in response to cellular stress is due to an enhancement in its stability, which is associated with an increase in its interaction with fibrillarin. Collectively, these results identify a role for SNORD80 in guiding 2'-O-methylation to stabilize GAS5. This uncovers a feedforward regulatory loop at the <i>GAS5</i> gene locus in response to cellular stress and sheds light on posttranscriptional mechanisms governing lncRNA expression.

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Journal
Proceedings of the National Academy of Sciences
Published
2025-02-13
DOI
https://doi.org/10.1073/pnas.2418996122
Citations
2
Primary Topic
Cancer-related molecular mechanisms research
Type
article
Field-Weighted Citation Impact
1.87

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article

SNORD80-guided 2’-O-methylation stabilizes the lncRNA GAS5 to regulate cellular stress responses

Xiao Hong Zhao, Man Man Han, Deng Tang, Jacob Netherton et al.
2 citations
Proceedings of the National Academy of Sciences
Cancer-related molecular mechanisms research
1.87
article

SNORD80-guided 2’-O-methylation stabilizes the lncRNA GAS5 to regulate cellular stress responses

Xiao Hong Zhao, Man Man Han, Deng Tang, Jacob Netherton, Meng Yao Zhang, Mark A. Baker, Xu Dong Zhang, Liang Xu, L. Zhang, Tao Liu, Teng Liu, Yan Ye, Lei Jin, Yi Yue, Tianli Fan, Kai Hong Ye, Yuan Yuan Zhang, Rachel A. Ogle, Yu Fang Wang, Siqi Lan, Jiezhen Yang
article en
2 citations

Abstract

The introns of the gene encoding the long noncoding RNA (lncRNA) GAS5 host up to 10 C/D box small nucleolar RNAs (snoRNAs). However, whether there is a regulatory and functional relationship between these snoRNAs and GAS5 is unknown. Here, we show that the expression of SNORD80, but not the other snoRNAs, parallels GAS5 expression and is regulated alongside GAS5 in response to cellular stress. The 2'-O-methylation at the A496 site, located within a segment of GAS5 complementing the conserved RNA-binding region on SNORD80, promotes GAS5 stability and consequent upregulation. This methylation requires SNORD80, as it is diminished by knockdown of SNORD80 and increased by SNORD80 overexpression, similar to the effects of manipulating the expression of fibrillarin, the methyltransferase of the box C/D small nucleolar ribonucleoprotein particle (snoRNP). The upregulation of SNORD80 in response to cellular stress is due to an enhancement in its stability, which is associated with an increase in its interaction with fibrillarin. Collectively, these results identify a role for SNORD80 in guiding 2'-O-methylation to stabilize GAS5. This uncovers a feedforward regulatory loop at the <i>GAS5</i> gene locus in response to cellular stress and sheds light on posttranscriptional mechanisms governing lncRNA expression.

Proceedings of the National Academy of SciencesVol. 122(7)
Academy of Medical Sciences (GB), Translational Research Institute (AU), Sun Yat-sen University (CN), Anhui Medical University (CN), Fudan University (CN), West China Medical Center of Sichuan University (CN), UNSW Sydney (AU), Zhengzhou University (CN), Children's Cancer Institute Australia (AU), Zhongshan Hospital (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), Henan Provincial People's Hospital (CN), University of Newcastle Australia (AU)
National Natural Science Foundation of China, Medical Research Council, National Health and Medical Research Council, Cancer Council NSW
Openalex Percentile: Top 17%
Cancer-related molecular mechanisms research
1.87
DOIOpen Access PDFOpenAlex
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