Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma
Abstract Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unkn...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45979-5 |
| _version_ | 1797273939412516864 |
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| author | Xing Cheng Jing An Jitong Lou Qisheng Gu Weimin Ding Gaith Nabil Droby Yilin Wang Chenghao Wang Yanzhe Gao Jay Ramanlal Anand Abigail Shelton Andrew Benson Satterlee Breanna Mann Yun-Chung Hsiao Chih-Wei Liu Kun Lu Shawn Hingtgen Jiguang Wang Zhaoliang Liu C. Ryan Miller Di Wu Cyrus Vaziri Yang Yang |
| author_facet | Xing Cheng Jing An Jitong Lou Qisheng Gu Weimin Ding Gaith Nabil Droby Yilin Wang Chenghao Wang Yanzhe Gao Jay Ramanlal Anand Abigail Shelton Andrew Benson Satterlee Breanna Mann Yun-Chung Hsiao Chih-Wei Liu Kun Lu Shawn Hingtgen Jiguang Wang Zhaoliang Liu C. Ryan Miller Di Wu Cyrus Vaziri Yang Yang |
| author_sort | Xing Cheng |
| collection | DOAJ |
| description | Abstract Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides an aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM. |
| first_indexed | 2024-03-07T14:51:17Z |
| format | Article |
| id | doaj.art-30b03460503c40948e61ba53f8ff91ba |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:51:17Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-30b03460503c40948e61ba53f8ff91ba2024-03-05T19:38:42ZengNature PortfolioNature Communications2041-17232024-03-0115112010.1038/s41467-024-45979-5Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastomaXing Cheng0Jing An1Jitong Lou2Qisheng Gu3Weimin Ding4Gaith Nabil Droby5Yilin Wang6Chenghao Wang7Yanzhe Gao8Jay Ramanlal Anand9Abigail Shelton10Andrew Benson Satterlee11Breanna Mann12Yun-Chung Hsiao13Chih-Wei Liu14Kun Lu15Shawn Hingtgen16Jiguang Wang17Zhaoliang Liu18C. Ryan Miller19Di Wu20Cyrus Vaziri21Yang Yang22Department of Pathology and Laboratory Medicine, University of North CarolinaDepartment of Pathology and Laboratory Medicine, University of North CarolinaDepartment of Biostatistics, University of North CarolinaShanghai Institute of Immunity and Infection, Chinese Academy of SciencesLineberger Comprehensive Cancer Center, University of North CarolinaDepartment of Pathology and Laboratory Medicine, University of North CarolinaDepartment of Pathology and Laboratory Medicine, University of North CarolinaDepartment of Biostatistics, University of North CarolinaDepartment of Pathology and Laboratory Medicine, University of North CarolinaDepartment of Pathology and Laboratory Medicine, University of North CarolinaDepartment of Pathology and Laboratory Medicine, University of North CarolinaEshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North CarolinaEshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North CarolinaDepartment of Environmental Sciences and Engineering, University of North Carolina at Chapel HillDepartment of Environmental Sciences and Engineering, University of North Carolina at Chapel HillDepartment of Environmental Sciences and Engineering, University of North Carolina at Chapel HillEshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North CarolinaDivision of Life Science, Department of Chemical and Biological Engineering, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and TechnologyInstitute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Sciences, Harbin Medical UniversityDepartment of Pathology and Laboratory Medicine, University of North CarolinaDepartment of Biostatistics, University of North CarolinaDepartment of Pathology and Laboratory Medicine, University of North CarolinaDepartment of Pathology and Laboratory Medicine, University of North CarolinaAbstract Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides an aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.https://doi.org/10.1038/s41467-024-45979-5 |
| spellingShingle | Xing Cheng Jing An Jitong Lou Qisheng Gu Weimin Ding Gaith Nabil Droby Yilin Wang Chenghao Wang Yanzhe Gao Jay Ramanlal Anand Abigail Shelton Andrew Benson Satterlee Breanna Mann Yun-Chung Hsiao Chih-Wei Liu Kun Lu Shawn Hingtgen Jiguang Wang Zhaoliang Liu C. Ryan Miller Di Wu Cyrus Vaziri Yang Yang Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma Nature Communications |
| title | Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma |
| title_full | Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma |
| title_fullStr | Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma |
| title_full_unstemmed | Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma |
| title_short | Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma |
| title_sort | trans lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma |
| url | https://doi.org/10.1038/s41467-024-45979-5 |
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