Phosphorylation of SIRT7 by ATM causes DNA mismatch repair downregulation and adaptive mutability during chemotherapy
Summary: Drug resistance significantly limits the efficacy of chemotherapy. The DNA mismatch repair (MMR) system maintains genomic stability by correcting DNA errors. During DNA-damaging treatments, cancer cells transiently increase their adaptive mutability, also known as microsatellite instability...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725000403 |
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| author | Lianhui Sun Guangjian Fan Zhuqing Zhang Dong Chang Xiaoyu Zhang Tongqing Zhang Jichuan Geng Xiaoxia Zhang Menghan Lin Chen Hu Jiaqi Zhou Mengxue Wang Liu Cao Mary Zhang Baokun He Shengping Zhang Chuangui Wang |
| author_facet | Lianhui Sun Guangjian Fan Zhuqing Zhang Dong Chang Xiaoyu Zhang Tongqing Zhang Jichuan Geng Xiaoxia Zhang Menghan Lin Chen Hu Jiaqi Zhou Mengxue Wang Liu Cao Mary Zhang Baokun He Shengping Zhang Chuangui Wang |
| author_sort | Lianhui Sun |
| collection | DOAJ |
| description | Summary: Drug resistance significantly limits the efficacy of chemotherapy. The DNA mismatch repair (MMR) system maintains genomic stability by correcting DNA errors. During DNA-damaging treatments, cancer cells transiently increase their adaptive mutability, also known as microsatellite instability (MSI), to evade therapeutic pressure through MMR downregulation, conferring drug resistance. However, an understanding of the underlying mechanisms of MMR protein downregulation under DNA-damaging drugs remains limited. Our study reveals a negative correlation between SIRT7 protein levels and MMR core protein MSH2 levels in cervical and lung cancer tissues. SIRT7 destabilizes MSH2, promoting MSI and mutagenesis. Molecularly, DNA damage triggers ATM kinase-dependent phosphorylation and subcellular redistribution of SIRT7. Phosphorylated SIRT7 interacts with and deacetylates MSH2, impairing MMR, and inducing MSI and drug resistance. Our findings suggest that SIRT7 drives MMR downregulation under therapeutic stress and that ATM-dependent phosphorylation of SIRT7 may serve as a predictive biomarker for chemotherapeutic efficacy and a target for cancer treatment. |
| format | Article |
| id | doaj-art-cbe21f51cba243b780ebb50b4332b440 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-cbe21f51cba243b780ebb50b4332b4402025-02-06T05:11:32ZengElsevierCell Reports2211-12472025-02-01442115269Phosphorylation of SIRT7 by ATM causes DNA mismatch repair downregulation and adaptive mutability during chemotherapyLianhui Sun0Guangjian Fan1Zhuqing Zhang2Dong Chang3Xiaoyu Zhang4Tongqing Zhang5Jichuan Geng6Xiaoxia Zhang7Menghan Lin8Chen Hu9Jiaqi Zhou10Mengxue Wang11Liu Cao12Mary Zhang13Baokun He14Shengping Zhang15Chuangui Wang16Biomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, ChinaBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, ChinaBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, ChinaBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, ChinaBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, ChinaBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, ChinaBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, ChinaBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, ChinaBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, ChinaBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, ChinaBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, ChinaBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, ChinaHealth Sciences Institute, College of Basic Medical Sciences, China Medical University, Shenyang 110122, ChinaDepartment of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R., Detroit, MI 48201, USAInstitute of Chinese Materia Medica, The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong 518033, ChinaBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, China; Corresponding authorBiomedical Translational Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, China; Corresponding authorSummary: Drug resistance significantly limits the efficacy of chemotherapy. The DNA mismatch repair (MMR) system maintains genomic stability by correcting DNA errors. During DNA-damaging treatments, cancer cells transiently increase their adaptive mutability, also known as microsatellite instability (MSI), to evade therapeutic pressure through MMR downregulation, conferring drug resistance. However, an understanding of the underlying mechanisms of MMR protein downregulation under DNA-damaging drugs remains limited. Our study reveals a negative correlation between SIRT7 protein levels and MMR core protein MSH2 levels in cervical and lung cancer tissues. SIRT7 destabilizes MSH2, promoting MSI and mutagenesis. Molecularly, DNA damage triggers ATM kinase-dependent phosphorylation and subcellular redistribution of SIRT7. Phosphorylated SIRT7 interacts with and deacetylates MSH2, impairing MMR, and inducing MSI and drug resistance. Our findings suggest that SIRT7 drives MMR downregulation under therapeutic stress and that ATM-dependent phosphorylation of SIRT7 may serve as a predictive biomarker for chemotherapeutic efficacy and a target for cancer treatment.http://www.sciencedirect.com/science/article/pii/S2211124725000403CP: Molecular biologyCP: Cancer |
| spellingShingle | Lianhui Sun Guangjian Fan Zhuqing Zhang Dong Chang Xiaoyu Zhang Tongqing Zhang Jichuan Geng Xiaoxia Zhang Menghan Lin Chen Hu Jiaqi Zhou Mengxue Wang Liu Cao Mary Zhang Baokun He Shengping Zhang Chuangui Wang Phosphorylation of SIRT7 by ATM causes DNA mismatch repair downregulation and adaptive mutability during chemotherapy Cell Reports CP: Molecular biology CP: Cancer |
| title | Phosphorylation of SIRT7 by ATM causes DNA mismatch repair downregulation and adaptive mutability during chemotherapy |
| title_full | Phosphorylation of SIRT7 by ATM causes DNA mismatch repair downregulation and adaptive mutability during chemotherapy |
| title_fullStr | Phosphorylation of SIRT7 by ATM causes DNA mismatch repair downregulation and adaptive mutability during chemotherapy |
| title_full_unstemmed | Phosphorylation of SIRT7 by ATM causes DNA mismatch repair downregulation and adaptive mutability during chemotherapy |
| title_short | Phosphorylation of SIRT7 by ATM causes DNA mismatch repair downregulation and adaptive mutability during chemotherapy |
| title_sort | phosphorylation of sirt7 by atm causes dna mismatch repair downregulation and adaptive mutability during chemotherapy |
| topic | CP: Molecular biology CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725000403 |
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