Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma.

Autor:	Cheng X; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.; Department of Neuro-Oncology, Chongqing University Cancer Hospital, Chongqing, China., An J; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.; Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, China., Lou J; Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA.; Eli Lilly and Company, Indianapolis, IN, 46285, USA., Gu Q; Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China.; Department of Immunology, Université Paris Cité, Paris, France., Ding W; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.; Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China., Droby GN; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC, 27599, USA., Wang Y; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA., Wang C; Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA., Gao Y; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA., Anand JR; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA., Shelton A; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA., Satterlee AB; Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, NC, 27599, USA., Mann B; Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, NC, 27599, USA., Hsiao YC; Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA., Liu CW; Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA., Lu K; Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA., Hingtgen S; Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, NC, 27599, USA., Wang J; Division of Life Science, Department of Chemical and Biological Engineering, State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Hong Kong SAR, China.; Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong SAR, China., Liu Z; Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, China., Miller CR; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.; Department of Pathology, Division of Neuropathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA., Wu D; Department of Biostatistics, University of North Carolina, Chapel Hill, NC, 27599, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.; Division of Oral and Craniofacial Health Science, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Vaziri C; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA. cyrus_vaziri@med.unc.edu.; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA. cyrus_vaziri@med.unc.edu., Yang Y; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA. yangyang@email.unc.edu.; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA. yangyang@email.unc.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2024 Mar 04; Vol. 15 (1), pp. 1957. Date of Electronic Publication: 2024 Mar 04.
DOI:	10.1038/s41467-024-45979-5
Abstrakt:	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 O 6 mG (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. (© 2024. The Author(s).)
Databáze:	MEDLINE
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