R-loop formation contributes to mTORC1 activation-dependent DNA replication stress induced by p53 deficiency
DNA replication stress is a significant contributor to spontaneous DNA damage and genome instability. While the impact of p53 deficiency on increasing DNA replication stress is known, the specific molecular mechanism underlying this phenome...
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| Format: | Article |
| Language: | English |
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China Science Publishing & Media Ltd.
2024-11-01
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| Series: | Acta Biochimica et Biophysica Sinica |
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| Online Access: | https://www.sciengine.com/doi/10.3724/abbs.2024188 |
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| author | Li Xiaolei Yang Cheng Zhang Xiaohui Wang Feiyang Sun Longhua Zhang Wei Xu Xinping |
| author_facet | Li Xiaolei Yang Cheng Zhang Xiaohui Wang Feiyang Sun Longhua Zhang Wei Xu Xinping |
| author_sort | Li Xiaolei |
| collection | DOAJ |
| description | DNA replication stress is a significant contributor to spontaneous DNA damage and genome instability. While the impact of p53 deficiency on increasing DNA replication stress is known, the specific molecular mechanism underlying this phenomenon remains poorly understood. This study explores how p53 deficiency induces DNA replication stress by activating mTORC1 through R-loop formation, which is facilitated by the upregulation of RNR. Research has shown that p53 deficiency results in increased γH2AX expression and a higher mutation rate in the HPRT gene. Interestingly, these effects can be alleviated by rapamycin, an mTORC1 inhibitor. Additionally, rapamycin reduces the abundance of R-loop structures in p53KO cells, which is linked to mTORC1’s regulation of ribonucleotide reductase (RNR) level. These findings suggest that p53 deficiency-induced DNA replication stress relies on mTORC1 activation, with the upregulation of RNR expression and R-loop formation. Overall, this study underscores the importance of R-loops in mTORC1 activation-dependent DNA replication stress triggered by p53 deficiency. |
| format | Article |
| id | doaj-art-7144cac3b55a46149615849bb8726a7e |
| institution | Kabale University |
| issn | 1672-9145 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | China Science Publishing & Media Ltd. |
| record_format | Article |
| series | Acta Biochimica et Biophysica Sinica |
| spelling | doaj-art-7144cac3b55a46149615849bb8726a7e2025-01-17T05:58:29ZengChina Science Publishing & Media Ltd.Acta Biochimica et Biophysica Sinica1672-91452024-11-01561875188510.3724/abbs.202418820d259ccR-loop formation contributes to mTORC1 activation-dependent DNA replication stress induced by p53 deficiencyLi Xiaolei0Yang Cheng1Zhang Xiaohui2Wang Feiyang3Sun Longhua4Zhang Wei5Xu Xinping6["Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Disease, Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China","China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang 330200, China"]["Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Disease, Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China","Jiangxi Medical College, First Clinical Medical College, Nanchang University, Nanchang 330006, China"]["Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Disease, Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China","Department of Respiratory and Critical Care Medicine, Renmin Hospital of Shangrao, Shangrao 334000, China"]["Jiangxi Medical College, First Clinical Medical College, Nanchang University, Nanchang 330006, China"]["Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Disease, Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China","China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang 330200, China"]["Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Disease, Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China","China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang 330200, China"]["Jiangxi Provincial Key Laboratory of Respiratory Diseases, Jiangxi Institute of Respiratory Disease, Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China","China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang 330200, China"]DNA replication stress is a significant contributor to spontaneous DNA damage and genome instability. While the impact of p53 deficiency on increasing DNA replication stress is known, the specific molecular mechanism underlying this phenomenon remains poorly understood. This study explores how p53 deficiency induces DNA replication stress by activating mTORC1 through R-loop formation, which is facilitated by the upregulation of RNR. Research has shown that p53 deficiency results in increased γH2AX expression and a higher mutation rate in the HPRT gene. Interestingly, these effects can be alleviated by rapamycin, an mTORC1 inhibitor. Additionally, rapamycin reduces the abundance of R-loop structures in p53KO cells, which is linked to mTORC1’s regulation of ribonucleotide reductase (RNR) level. These findings suggest that p53 deficiency-induced DNA replication stress relies on mTORC1 activation, with the upregulation of RNR expression and R-loop formation. Overall, this study underscores the importance of R-loops in mTORC1 activation-dependent DNA replication stress triggered by p53 deficiency.https://www.sciengine.com/doi/10.3724/abbs.2024188p53mTORC1DNA replication stressR loopsRNR |
| spellingShingle | Li Xiaolei Yang Cheng Zhang Xiaohui Wang Feiyang Sun Longhua Zhang Wei Xu Xinping R-loop formation contributes to mTORC1 activation-dependent DNA replication stress induced by p53 deficiency Acta Biochimica et Biophysica Sinica p53 mTORC1 DNA replication stress R loops RNR |
| title | R-loop formation contributes to mTORC1 activation-dependent DNA replication stress induced by p53 deficiency |
| title_full | R-loop formation contributes to mTORC1 activation-dependent DNA replication stress induced by p53 deficiency |
| title_fullStr | R-loop formation contributes to mTORC1 activation-dependent DNA replication stress induced by p53 deficiency |
| title_full_unstemmed | R-loop formation contributes to mTORC1 activation-dependent DNA replication stress induced by p53 deficiency |
| title_short | R-loop formation contributes to mTORC1 activation-dependent DNA replication stress induced by p53 deficiency |
| title_sort | r loop formation contributes to mtorc1 activation dependent dna replication stress induced by p53 deficiency |
| topic | p53 mTORC1 DNA replication stress R loops RNR |
| url | https://www.sciengine.com/doi/10.3724/abbs.2024188 |
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