{"doi":"10.1073/pnas.2309047120","title":"PARP7-mediated ADP-ribosylation of FRA1 promotes cancer cell growth by repressing IRF1- and IRF3-dependent apoptosis","abstract":"<jats:p>PARP7 was reported to promote tumor growth in a cell-autonomous manner and by repressing the antitumor immune response. Nevertheless, the molecular mechanism of how PARP7-mediated ADP-ribosylation exerts these effects in cancer cells remains elusive. Here, we identified PARP7 as a nuclear and cysteine-specific mono-ADP-ribosyltransferase that modifies targets critical for regulating transcription, including the AP-1 transcription factor FRA1. Loss of FRA1 ADP-ribosylation via PARP7 inhibition by RBN-2397 or mutation of the ADP-ribosylation site C97 increased FRA1 degradation by the proteasome via PSMC3. The reduction in FRA1 protein levels promoted IRF1- and IRF3-dependent cytokine as well as proapoptotic gene expression, culminating in CASP8-mediated apoptosis. Furthermore, high PARP7 expression was indicative of the PARP7 inhibitor response in FRA1-positive lung and breast cancer cells. Collectively, our findings highlight the connected roles of PARP7 and FRA1 and emphasize the clinical potential of PARP7 inhibitors for FRA1-driven cancers.</jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":629227,"datarank":0.5676284450877392,"base_score":3.784189633918261,"endowment":3.784189633918261,"self_citation_contribution":0.5676284450877392,"citation_network_contribution":0.0,"self_endowment_contribution":0.5676284450877392,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":43,"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":669579,"name":"Flurina Böhi","orcid":"0009-0002-1752-8437","position":1,"is_corresponding":false},{"id":1629466,"name":"Kathrin Nowak","orcid":null,"position":2,"is_corresponding":false},{"id":1629467,"name":"Deena M. Leslie Pedrioli","orcid":null,"position":3,"is_corresponding":false},{"id":376828,"name":"Michael O. Hottiger","orcid":"0000-0002-7323-2270","position":4,"is_corresponding":false},{"id":1629465,"name":"Patrick Manetsch","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"PARP7-mediated ADP-ribosylation of FRA1 promotes cancer cell growth by repressing IRF1- and IRF3-dependent apoptosis","abstract":"<jats:p>PARP7 was reported to promote tumor growth in a cell-autonomous manner and by repressing the antitumor immune response. Nevertheless, the molecular mechanism of how PARP7-mediated ADP-ribosylation exerts these effects in cancer cells remains elusive. Here, we identified PARP7 as a nuclear and cysteine-specific mono-ADP-ribosyltransferase that modifies targets critical for regulating transcription, including the AP-1 transcription factor FRA1. Loss of FRA1 ADP-ribosylation via PARP7 inhibition by RBN-2397 or mutation of the ADP-ribosylation site C97 increased FRA1 degradation by the proteasome via PSMC3. The reduction in FRA1 protein levels promoted IRF1- and IRF3-dependent cytokine as well as proapoptotic gene expression, culminating in CASP8-mediated apoptosis. Furthermore, high PARP7 expression was indicative of the PARP7 inhibitor response in FRA1-positive lung and breast cancer cells. Collectively, our findings highlight the connected roles of PARP7 and FRA1 and emphasize the clinical potential of PARP7 inhibitors for FRA1-driven cancers.</jats:p>","is_dataset_classified":null,"base_score":3.784189633918261,"endowment":3.784189633918261,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38011562","pmcid":"PMC10710093","openalex_id":"https://openalex.org/W4389042136","authors":[],"funders":[{"funder_name":"Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung","grant_id":"IZLIZ3_200237","title":null},{"funder_name":"Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung","grant_id":"310030_205202","title":null},{"funder_name":"Swiss National Science Foundation","grant_id":"205202","title":"Understanding the regulation of mitochondrial ADP-ribosylation and its impact on macrophage function"},{"funder_name":"Swiss National Science Foundation","grant_id":"200237","title":"Investigating the molecular mechanisms of the ADP-ribosyltransferase PARP6 in manifestation and progression of heart failure"},{"funder_name":"Swiss National Science Foundation","grant_id":"310030","title":null}],"total_grants":5,"fwci":4.9535,"citation_percentile":0.96705783,"influential_citations":0,"citation_trend":[{"year":2023,"count":1},{"year":2024,"count":9},{"year":2025,"count":22},{"year":2026,"count":11}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1073/pnas.2309047120","host_type":"journal"},{"url":"https://doi.org/10.1073/pnas.2309047120","host_type":"publisher"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.2309047120","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38011562","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/10710093","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10710093/pdf/pnas.202309047.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC10710093","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC10710093?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1073/pnas.2309047120","host_type":""}],"fields_of_study":["PARP inhibition in cancer therapy","DNA Repair Mechanisms","Cell death mechanisms and regulation","0301 basic medicine","03 medical and health sciences","Humans","ADP Ribose Transferases","ADP-Ribosylation","Apoptosis","Cell Transformation, Neoplastic","Gene Expression Regulation","Interferon Regulatory Factor-1","Interferon Regulatory Factor-3","Neoplasms","Nucleoside Transport Proteins","Proto-Oncogene Proteins c-fos","Fos-Related Antigen 1"],"mesh_terms":["ADP-Ribosylation","Fos-Related Antigen 1","Cell Transformation, Neoplastic","Gene Expression Regulation","Humans","Neoplasms","Proto-Oncogene Proteins c-fos","Apoptosis","Nucleoside Transport Proteins","ADP Ribose Transferases","Interferon Regulatory Factor-3","Interferon Regulatory Factor-1"],"keywords":["Transcription factor","IRF3","Biology","Cancer research","IRF1","Apoptosis","Cell biology","Gene","Biochemistry","Cancer","Adp-ribosylation","Fra1","Proteasomal Protein Degradation","Parp7","ADP Ribose Transferases","Fos-Related Antigen 1","Nucleoside Transport Proteins","Biological Sciences","Cell Transformation, Neoplastic","Gene Expression Regulation","Neoplasms","Humans","Interferon Regulatory Factor-3","Proto-Oncogene Proteins c-fos","Interferon Regulatory Factor-1"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-05T17:39:21.112627Z","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":[]}