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.
Nat Commun. 2024 Mar 4;15(1):1957. doi: 10.1038/s41467-024-45979-5.
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 OmG (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.
几乎所有的胶质母细胞瘤（GBM）对化疗药物替莫唑胺（TMZ）都具有内在的耐药性，或者获得了导致化疗耐药和复发的治疗诱导突变。负责 GBM 化疗耐药和高突变的基因组维持机制尚不清楚。我们表明，E3 泛素连接酶 RAD18（TLS 的近端调节剂）在 TMZ 处理的 GBM 细胞中以错配修复（MMR）依赖性方式被激活，促进复制后间隙填充和存活。一项无偏见的 CRISPR 筛选提供了 GBM 用于耐受 TMZ 遗传毒性的 RAD18 相互作用的 DNA 损伤反应（DDR）途径的鸟瞰图。对 TMZ 处理的 GBM 的突变特征的分析揭示了 RAD18 在 OmG（最毒的 TMZ 诱导损伤）的无错误旁路和其他 TMZ 诱导损伤的易错旁路中的作用。我们对复发性 GBM 患者样本的分析确立了低 RAD18 表达与高突变之间的相关性。总之，我们定义了 TMZ 处理的 GBM 的标志性肿瘤发生表型的分子基础。
