{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Kedar PS"],"funding":["Intramural NIH HHS"],"pagination":["360-8"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC3307909"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["10(3)"],"pubmed_abstract":["Treatment of base excision repair-proficient mouse fibroblasts with the DNA alkylating agent methyl methanesulfonate (MMS) and a small molecule inhibitor of PARP-1 results in a striking cell killing phenotype, as previously reported. Earlier studies showed that the mechanism of cell death is apoptosis and requires DNA replication, expression of PARP-1, and an intact S-phase checkpoint cell signaling system. It is proposed that activity-inhibited PARP-1 becomes immobilized at DNA repair intermediates, and that this blocks DNA repair and interferes with DNA replication, eventually promoting an S-phase checkpoint and G(2)-M block. Here we report studies designed to evaluate the prediction that inhibited PARP-1 remains DNA associated in cells undergoing repair of alkylation-induced damage. Using chromatin immunoprecipitation with anti-PARP-1 antibody and qPCR for DNA quantification, a higher level of DNA was found associated with PARP-1 in cells treated with MMS plus PARP inhibitor than in cells without inhibitor treatment. These results have implications for explaining the extreme hypersensitivity phenotype after combination treatment with MMS and a PARP inhibitor."],"journal":["Molecular cancer research : MCR"],"pubmed_title":["Increased PARP-1 association with DNA in alkylation damaged, PARP-inhibited mouse fibroblasts."],"pmcid":["PMC3307909"],"funding_grant_id":["Z01 ES050159-11","Z01 ES050159"],"pubmed_authors":["Horton JK","Kedar PS","Wilson SH","Stefanick DF"],"additional_accession":[]},"is_claimable":false,"name":"Increased PARP-1 association with DNA in alkylation damaged, PARP-inhibited mouse fibroblasts.","description":"Treatment of base excision repair-proficient mouse fibroblasts with the DNA alkylating agent methyl methanesulfonate (MMS) and a small molecule inhibitor of PARP-1 results in a striking cell killing phenotype, as previously reported. Earlier studies showed that the mechanism of cell death is apoptosis and requires DNA replication, expression of PARP-1, and an intact S-phase checkpoint cell signaling system. It is proposed that activity-inhibited PARP-1 becomes immobilized at DNA repair intermediates, and that this blocks DNA repair and interferes with DNA replication, eventually promoting an S-phase checkpoint and G(2)-M block. Here we report studies designed to evaluate the prediction that inhibited PARP-1 remains DNA associated in cells undergoing repair of alkylation-induced damage. Using chromatin immunoprecipitation with anti-PARP-1 antibody and qPCR for DNA quantification, a higher level of DNA was found associated with PARP-1 in cells treated with MMS plus PARP inhibitor than in cells without inhibitor treatment. These results have implications for explaining the extreme hypersensitivity phenotype after combination treatment with MMS and a PARP inhibitor.","dates":{"release":"2012-01-01T00:00:00Z","publication":"2012 Mar","modification":"2024-11-14T10:44:50.968Z","creation":"2019-06-05T17:09:43Z"},"accession":"S-EPMC3307909","cross_references":{"pubmed":["22246237"],"doi":["10.1158/1541-7786.mcr-11-0477","10.1158/1541-7786.MCR-11-0477"]}}