Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality
Summary: Overexpression of USP7 and HDM2 inactivates P53 signaling in tumor cells and facilitates their progression, but suppression of these targets by conventional strategies to reactivate P53 function remains a challenge. We applied polyQ sequences and target-interacting peptides to engineer poly...
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Elsevier
2025-03-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225002858 |
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| author | Xiang-Le Zhang Hong-Wei Yue Ya-Jun Liu Jian-Yang Wang Heng-Tong Duan Yin-Hu Liu Lei-Lei Jiang Hong-Yu Hu |
| author_facet | Xiang-Le Zhang Hong-Wei Yue Ya-Jun Liu Jian-Yang Wang Heng-Tong Duan Yin-Hu Liu Lei-Lei Jiang Hong-Yu Hu |
| author_sort | Xiang-Le Zhang |
| collection | DOAJ |
| description | Summary: Overexpression of USP7 and HDM2 inactivates P53 signaling in tumor cells and facilitates their progression, but suppression of these targets by conventional strategies to reactivate P53 function remains a challenge. We applied polyQ sequences and target-interacting peptides to engineer polyQ fusion proteins that specifically sequester the targets, hence depleting their availabilities and modulating the P53 functionality. We have revealed that the designer fusion Atx793Q-N172-IRF (IRF sequence: SPGEGPSGTG) sequesters USP7 and/or HDM2 into aggregates and thereby increases the P53 level, but it depends on the IRF repeats fused, suggesting that depletion of the USP7 availability plays a dual role in controlling P53 stability. Direct sequestration of HDM2 by Atx793Q-N172-PMI (PMI: TSFAEYWNLLSP) remarkably reduces the protein level of soluble HDM2 and hence increases the P53 level, which consequently up-regulates expression of the downstream genes. The polyQ-fusion strategy is feasible to modulate the P53 stability and functionality, furnishing a therapeutic potential for cancers. |
| format | Article |
| id | doaj-art-28b95e4d183441eea9f0d2828e4a36ee |
| institution | OA Journals |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-28b95e4d183441eea9f0d2828e4a36ee2025-08-20T02:11:05ZengElsevieriScience2589-00422025-03-0128311202510.1016/j.isci.2025.112025Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionalityXiang-Le Zhang0Hong-Wei Yue1Ya-Jun Liu2Jian-Yang Wang3Heng-Tong Duan4Yin-Hu Liu5Lei-Lei Jiang6Hong-Yu Hu7Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. ChinaKey Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. ChinaKey Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. ChinaKey Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. ChinaKey Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. ChinaKey Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China; University of Chinese Academy of Sciences, Beijing 100049, P.R. ChinaKey Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. ChinaKey Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, P.R. China; Corresponding authorSummary: Overexpression of USP7 and HDM2 inactivates P53 signaling in tumor cells and facilitates their progression, but suppression of these targets by conventional strategies to reactivate P53 function remains a challenge. We applied polyQ sequences and target-interacting peptides to engineer polyQ fusion proteins that specifically sequester the targets, hence depleting their availabilities and modulating the P53 functionality. We have revealed that the designer fusion Atx793Q-N172-IRF (IRF sequence: SPGEGPSGTG) sequesters USP7 and/or HDM2 into aggregates and thereby increases the P53 level, but it depends on the IRF repeats fused, suggesting that depletion of the USP7 availability plays a dual role in controlling P53 stability. Direct sequestration of HDM2 by Atx793Q-N172-PMI (PMI: TSFAEYWNLLSP) remarkably reduces the protein level of soluble HDM2 and hence increases the P53 level, which consequently up-regulates expression of the downstream genes. The polyQ-fusion strategy is feasible to modulate the P53 stability and functionality, furnishing a therapeutic potential for cancers.http://www.sciencedirect.com/science/article/pii/S2589004225002858BiochemistryProtein structure aspectsCancer |
| spellingShingle | Xiang-Le Zhang Hong-Wei Yue Ya-Jun Liu Jian-Yang Wang Heng-Tong Duan Yin-Hu Liu Lei-Lei Jiang Hong-Yu Hu Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality iScience Biochemistry Protein structure aspects Cancer |
| title | Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality |
| title_full | Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality |
| title_fullStr | Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality |
| title_full_unstemmed | Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality |
| title_short | Designer polyQ fusion proteins sequester USP7/HDM2 for modulating P53 functionality |
| title_sort | designer polyq fusion proteins sequester usp7 hdm2 for modulating p53 functionality |
| topic | Biochemistry Protein structure aspects Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225002858 |
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