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

ABSTRACT:

Background

Temozolomide (TMZ) resistance in glioblastoma multiforme (GBM) is mediated by the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT). 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 (PARP).

Methods

MGMT-PARP interaction was detected by co-immunoprecipitation. PARylation of MGMT and PARP was detected

SUBMITTER: Wu S 

PROVIDER: S-EPMC8168825 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature