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

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 () and Yang Yang ()
Additional contact information
Xing Cheng: University of North Carolina
Jing An: University of North Carolina
Jitong Lou: University of North Carolina
Qisheng Gu: Chinese Academy of Sciences
Weimin Ding: University of North Carolina
Gaith Nabil Droby: University of North Carolina
Yilin Wang: University of North Carolina
Chenghao Wang: University of North Carolina
Yanzhe Gao: University of North Carolina
Jay Ramanlal Anand: University of North Carolina
Abigail Shelton: University of North Carolina
Andrew Benson Satterlee: University of North Carolina
Breanna Mann: University of North Carolina
Yun-Chung Hsiao: University of North Carolina at Chapel Hill
Chih-Wei Liu: University of North Carolina at Chapel Hill
Kun Lu: University of North Carolina at Chapel Hill
Shawn Hingtgen: University of North Carolina
Jiguang Wang: The Hong Kong University of Science and Technology
Zhaoliang Liu: Harbin Medical University
C. Ryan Miller: University of North Carolina
Di Wu: University of North Carolina
Cyrus Vaziri: University of North Carolina
Yang Yang: University of North Carolina

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45979-5

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