Reduced UPF1 levels in senescence impair nonsense-mediated mRNA decay
Abstract Cells regulate gene expression through various RNA regulatory mechanisms, and this regulation often becomes less efficient with age, contributing to accelerated aging and various age-related diseases. Nonsense-mediated mRNA decay (NMD), a well-characterized RNA surveillance mechanism, degra...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07502-4 |
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| author | Dahyeon Koh Yebin Lee Kyuchan Kim Hyeong Bin Jeon Chaehwan Oh Sangik Hwang Minjung Lim Kwang-Pyo Lee Yeonkyoung Park Yong Ryoul Yang Yoon Ki Kim Donghwan Shim Myriam Gorospe Ji Heon Noh Kyoung Mi Kim |
| author_facet | Dahyeon Koh Yebin Lee Kyuchan Kim Hyeong Bin Jeon Chaehwan Oh Sangik Hwang Minjung Lim Kwang-Pyo Lee Yeonkyoung Park Yong Ryoul Yang Yoon Ki Kim Donghwan Shim Myriam Gorospe Ji Heon Noh Kyoung Mi Kim |
| author_sort | Dahyeon Koh |
| collection | DOAJ |
| description | Abstract Cells regulate gene expression through various RNA regulatory mechanisms, and this regulation often becomes less efficient with age, contributing to accelerated aging and various age-related diseases. Nonsense-mediated mRNA decay (NMD), a well-characterized RNA surveillance mechanism, degrades aberrant mRNAs with premature termination codons (PTCs) to prevent the synthesis of truncated proteins. While the role of NMD in cancer and developmental and genetic diseases is well documented, its implications in human aging remain largely unexplored. This study reveals a significant decline in the levels of the protein UPF1, a key player in NMD, during cellular senescence. Additionally, NMD substrates accumulate in senescent cells, along with decreased levels of cap-binding protein 80/20 (CBP80/20)-dependent translation (CT) factors and reduced binding to active polysomes, indicating reduced efficiency of NMD. Moreover, knockdown of UPF1 in proliferating WI-38 cells induces senescence, as evidenced by increased senescence-associated β-galactosidase activity, alterations in senescence-associated molecular markers, increased endogenous γ-H2AX levels, and reduced cell proliferation. These findings suggest that the decline in UPF1 levels during cellular senescence accelerates the senescent phenotype by impairing NMD activity and the consequent accumulation of abnormal mRNA. |
| format | Article |
| id | doaj-art-335695bf4076440b94ea3c6803c68b45 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-335695bf4076440b94ea3c6803c68b452025-01-19T12:35:38ZengNature PortfolioCommunications Biology2399-36422025-01-018111310.1038/s42003-025-07502-4Reduced UPF1 levels in senescence impair nonsense-mediated mRNA decayDahyeon Koh0Yebin Lee1Kyuchan Kim2Hyeong Bin Jeon3Chaehwan Oh4Sangik Hwang5Minjung Lim6Kwang-Pyo Lee7Yeonkyoung Park8Yong Ryoul Yang9Yoon Ki Kim10Donghwan Shim11Myriam Gorospe12Ji Heon Noh13Kyoung Mi Kim14Department of Biological Sciences, Chungnam National UniversityDepartment of Biological Sciences, Chungnam National UniversityDepartment of Bio-AI Convergence, Chungnam National UniversityDepartment of Biological Sciences, Chungnam National UniversityDepartment of Biological Sciences, Chungnam National UniversityMolecular Aging Biology Laboratory (MABL), Department of Biochemistry, College of Natural Science, Chungnam National UniversityDepartment of Biological Sciences, Chungnam National UniversityAging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Department of Biological Sciences, Korea Advanced Institute of Science and TechnologyAging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)Department of Biological Sciences, Korea Advanced Institute of Science and TechnologyDepartment of Biological Sciences, Chungnam National UniversityLaboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of HealthMolecular Aging Biology Laboratory (MABL), Department of Biochemistry, College of Natural Science, Chungnam National UniversityDepartment of Biological Sciences, Chungnam National UniversityAbstract Cells regulate gene expression through various RNA regulatory mechanisms, and this regulation often becomes less efficient with age, contributing to accelerated aging and various age-related diseases. Nonsense-mediated mRNA decay (NMD), a well-characterized RNA surveillance mechanism, degrades aberrant mRNAs with premature termination codons (PTCs) to prevent the synthesis of truncated proteins. While the role of NMD in cancer and developmental and genetic diseases is well documented, its implications in human aging remain largely unexplored. This study reveals a significant decline in the levels of the protein UPF1, a key player in NMD, during cellular senescence. Additionally, NMD substrates accumulate in senescent cells, along with decreased levels of cap-binding protein 80/20 (CBP80/20)-dependent translation (CT) factors and reduced binding to active polysomes, indicating reduced efficiency of NMD. Moreover, knockdown of UPF1 in proliferating WI-38 cells induces senescence, as evidenced by increased senescence-associated β-galactosidase activity, alterations in senescence-associated molecular markers, increased endogenous γ-H2AX levels, and reduced cell proliferation. These findings suggest that the decline in UPF1 levels during cellular senescence accelerates the senescent phenotype by impairing NMD activity and the consequent accumulation of abnormal mRNA.https://doi.org/10.1038/s42003-025-07502-4 |
| spellingShingle | Dahyeon Koh Yebin Lee Kyuchan Kim Hyeong Bin Jeon Chaehwan Oh Sangik Hwang Minjung Lim Kwang-Pyo Lee Yeonkyoung Park Yong Ryoul Yang Yoon Ki Kim Donghwan Shim Myriam Gorospe Ji Heon Noh Kyoung Mi Kim Reduced UPF1 levels in senescence impair nonsense-mediated mRNA decay Communications Biology |
| title | Reduced UPF1 levels in senescence impair nonsense-mediated mRNA decay |
| title_full | Reduced UPF1 levels in senescence impair nonsense-mediated mRNA decay |
| title_fullStr | Reduced UPF1 levels in senescence impair nonsense-mediated mRNA decay |
| title_full_unstemmed | Reduced UPF1 levels in senescence impair nonsense-mediated mRNA decay |
| title_short | Reduced UPF1 levels in senescence impair nonsense-mediated mRNA decay |
| title_sort | reduced upf1 levels in senescence impair nonsense mediated mrna decay |
| url | https://doi.org/10.1038/s42003-025-07502-4 |
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