PARP-mediated PARylation of MGMT is critical to promote repair of temozolomide-induced O6-methylguanine DNA damage in glioblastoma

Jan 12, 2021Neuro-oncology

PARP helps MGMT repair chemotherapy-caused DNA damage in brain cancer

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Abstract

inhibition reduced activity, potentially sensitizing glioblastoma to TMZ treatment.

PARP physically binds to MGMT and modifies it in response to TMZ treatment.
Modification of MGMT by PARP is necessary for MGMT to effectively repair DNA damage caused by TMZ.
Inhibition of PARP decreased the binding and modification of MGMT, reducing its ability to repair DNA.
Restoration of TMZ sensitivity was observed in mouse models with MGMT-expressing glioblastoma following PARP inhibition.

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BACKGROUND: Temozolomide (TMZ) resistance in glioblastoma multiforme (GBM) is mediated by the DNA repair protein O6-methylguanine DNA methyltransferase (). MGMT promoter methylation (occurs in about 40% of 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 ().

METHODS: MGMT-PARP interaction was detected by co-immunoprecipitation. PARylation of MGMT and PARP was detected by co-immunoprecipitation with anti-PAR antibody. O6-methylguanine (O6-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 O6-MetG adducts from DNA after TMZ treatment. PARP inhibitors reduced PARP-MGMT binding and MGMT PARylation, silencing MGMT activity to repair O6-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.

Key numbers

6 of 13

Methylation Rate

promoter methylation detected in GSC lines.

27.4%

Synergistic Effect Increase

Excess over Bliss score indicating synergy in + cells treated with talazoparib and TMZ.

50 mg/kg/day

Tumor Growth Inhibition

Dosage of TMZ administered in mouse models.

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PARP-mediated PARylation of MGMT is critical to promote repair of temozolomide-induced O6-methylguanine DNA damage in glioblastoma

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