Trans-Lesion Synthesis and Mismatch Repair Pathway Crosstalk Defines Chemoresistance and Hypermutation Mechanisms in Glioblastoma.
Journal
bioRxiv : the preprint server for biology
Titre abrégé: bioRxiv
Pays: United States
ID NLM: 101680187
Informations de publication
Date de publication:
19 Oct 2023
19 Oct 2023
Historique:
pubmed:
31
10
2023
medline:
31
10
2023
entrez:
31
10
2023
Statut:
epublish
Résumé
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 a new 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
Identifiants
pubmed: 37905107
doi: 10.1101/2023.10.16.562506
pmc: PMC10614844
pii:
doi:
Types de publication
Preprint
Langues
eng
Subventions
Organisme : NCI NIH HHS
ID : P30 CA016086
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA229530
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA215347
Pays : United States
Organisme : NIEHS NIH HHS
ID : P42 ES031007
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001111
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES010126
Pays : United States
Organisme : NIH HHS
ID : S10 OD030223
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES009558
Pays : United States
Commentaires et corrections
Type : UpdateIn
Déclaration de conflit d'intérêts
COMPETING INTERESTS DECLARATION B.M., S.H., and A.S. have submitted a provisional patent application based on the OBSC work in this manuscript
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