{"doi":"10.1093/neuonc/noab003","title":"PARP-mediated PARylation of MGMT is critical to promote repair of temozolomide-induced O6-methylguanine DNA damage in glioblastoma","abstract":"<jats:title>Abstract</jats:title>\n               <jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>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).</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>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.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>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.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion</jats:title>\n                  <jats:p>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.</jats:p>\n               </jats:sec>","journal":"Neuro-Oncology","year":2021,"id":637028,"datarank":0.7515952941144385,"base_score":5.0106352940962555,"endowment":5.0106352940962555,"self_citation_contribution":0.7515952941144385,"citation_network_contribution":0.0,"self_endowment_contribution":0.7515952941144385,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":149,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":669773,"name":"Xiaolong Li","orcid":"0000-0002-8396-2912","position":1,"is_corresponding":false},{"id":246439,"name":"Feng Gao","orcid":"0000-0002-7539-6455","position":2,"is_corresponding":false},{"id":1653785,"name":"John F de Groot","orcid":null,"position":3,"is_corresponding":false},{"id":645069,"name":"Dimpy Koul","orcid":"0000-0001-5297-9220","position":4,"is_corresponding":false},{"id":1653788,"name":"W K Alfred Yung","orcid":null,"position":5,"is_corresponding":false},{"id":645705,"name":"Shaofang Wu","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"PARP-mediated PARylation of MGMT is critical to promote repair of temozolomide-induced O6-methylguanine DNA damage in glioblastoma","abstract":"<jats:title>Abstract</jats:title>\n               <jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>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).</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>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.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>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.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion</jats:title>\n                  <jats:p>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.</jats:p>\n               </jats:sec>","is_dataset_classified":null,"base_score":5.0106352940962555,"endowment":5.0106352940962555,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"33433610","pmcid":"PMC8168825","openalex_id":"https://openalex.org/W3119609126","authors":[],"funders":[{"funder_name":"W.K.A.Y. and a Cancer Center","grant_id":"CA016672","title":null},{"funder_name":"NCI NIH HHS","grant_id":"P30 CA016672","title":null},{"funder_name":"National Brain Tumor Society","grant_id":"","title":null}],"total_grants":3,"fwci":7.4583,"citation_percentile":0.98414813,"influential_citations":0,"citation_trend":[{"year":2021,"count":6},{"year":2022,"count":31},{"year":2023,"count":27},{"year":2024,"count":28},{"year":2025,"count":38},{"year":2026,"count":19}],"oa_status":"hybrid","license":"cc-by-nc","oa_locations":[{"url":"https://academic.oup.com/neuro-oncology/article-pdf/23/6/920/38435715/noab003.pdf","host_type":"journal"},{"url":"https://academic.oup.com/neuro-oncology/article-pdf/23/6/920/38435715/noab003.pdf","host_type":"publisher"},{"url":"http://academic.oup.com/neuro-oncology/advance-article-pdf/doi/10.1093/neuonc/noab003/36275124/noab003.pdf","host_type":"publisher"},{"url":"http://academic.oup.com/neuro-oncology/article-pdf/23/6/920/38435715/noab003.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/neuonc/noab003","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/33433610","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8168825","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8168825","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8168825?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["PARP inhibition in cancer therapy","Glioma Diagnosis and Treatment","DNA Repair Mechanisms","Animals","Antineoplastic Agents, Alkylating","Cell Line, Tumor","DNA Damage","DNA Modification Methylases","DNA Repair Enzymes","Dacarbazine","Glioblastoma","Guanine","Humans","Mice","Poly ADP Ribosylation","Poly(ADP-ribose) Polymerase Inhibitors","Temozolomide","Tumor Suppressor Proteins"],"mesh_terms":["Poly(ADP-ribose) Polymerase Inhibitors","Poly ADP Ribosylation","Temozolomide","Animals","Dacarbazine","DNA Damage","Glioblastoma","Guanine","Humans","DNA Modification Methylases","Antineoplastic Agents, Alkylating","Tumor Suppressor Proteins","DNA Repair Enzymes","Cell Line, Tumor","Mice"],"keywords":["Temozolomide","O-6-methylguanine-DNA methyltransferase","Glioblastoma","DNA repair","Cancer research","Poly ADP ribose polymerase","DNA damage","DNA Damage Repair","Oncology","DNA","Medicine","Chemistry","Methyltransferase","Biochemistry","Methylation","PARP","Tmz Resistance","Mgmt Parylation"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-06T18:10:53.239483Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}