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

Author:

Cheng XingORCID,An JingORCID,Lou JitongORCID,Gu QishengORCID,Ding Weimin,Droby Gaith NabilORCID,Wang YilinORCID,Wang Chenghao,Gao Yanzhe,Anand Jay RamanlalORCID,Shelton Abigail,Satterlee Andrew Benson,Mann BreannaORCID,Hsiao Yun-ChungORCID,Liu Chih-WeiORCID,Lu Kun,Hingtgen ShawnORCID,Wang JiguangORCID,Liu ZhaoliangORCID,Miller C. RyanORCID,Wu DiORCID,Vaziri CyrusORCID,Yang YangORCID

Abstract

AbstractAlmost 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.

Publisher

Springer Science and Business Media LLC

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