Abstract:
BACKGROUND:Temozolomide (TMZ) resistance in Glioblastoma (GBM) is mediated by the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). MGMT promoter methylation (occurs in about 40% patients) is associated with loss of MGMT expression (MGMT-) that compromises DNA repair, leading to a favorable response to TMZ therapy. The 60% of patients with unmethylated MGMT (MGMT+) GBM experience resistance to TMZ; in these patients, understanding the mechanism of MGMT mediated repair and modulating MGMT activity may lead to enhanced TMZ activity. Here, we report a novel mode of regulation of MGMT protein activity by poly-ADP-ribose polymerase (PARP). METHODS:MGMT-PARP interaction was detected by co-immunoprecipitation (IP). PARylation of MGMT and PARP was detected by co-immunoprecipitation with anti-PAR antibody. O 6-methylguanine (O 6-MetG) adducts were quantified by immunofluorescence assay. In vivo studies were conducted in mice to determine the effectiveness of PARP inhibition in sensitizing GBM to TMZ. RESULTS:We demonstrated that PARP physically binds with MGMT and PARylates MGMT in response to TMZ treatment. In addition, PARylation of MGMT by PARP is required for MGMT binding to chromatin to enhance the removal of O 6-MetG adducts from DNA after TMZ treatment. PARP inhibitors reduced PARP-MGMT binding and MGMT PARylation, silencing MGMT activity to repair O 6-MetG. PARP inhibition restored TMZ sensitivity in vivo in MGMT expressing GBM. CONCLUSION:This study demonstrated that PARylation of MGMT by PARP is critical for repairing TMZ-induced O6-MetG, and inhibition of PARylation by PARP inhibitor reduces MGMT function rendering sensitization to TMZ, providing a rationale for combining PARP inhibitors to sensitize TMZ in MGMT unmethylated GBM.
journal_name
Neuro Oncoljournal_title
Neuro-oncologyauthors
Wu S,Li X,Gao F,de Groot JF,Koul D,Yung WKAdoi
10.1093/neuonc/noab003subject
Has Abstractpub_date
2021-01-12 00:00:00eissn
1522-8517issn
1523-5866pii
6089123pub_type
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