{"doi":"10.1093/nar/gkad549","title":"DNA-PK is activated by SIRT2 deacetylation to promote DNA double-strand break repair by non-homologous end joining","abstract":"DNA-dependent protein kinase (DNA-PK) plays a critical role in non-homologous end joining (NHEJ), the predominant pathway that repairs DNA double-strand breaks (DSB) in response to ionizing radiation (IR) to govern genome integrity. The interaction of the catalytic subunit of DNA-PK (DNA-PKcs) with the Ku70/Ku80 heterodimer on DSBs leads to DNA-PK activation; however, it is not known if upstream signaling events govern this activation. Here, we reveal a regulatory step governing DNA-PK activation by SIRT2 deacetylation, which facilitates DNA-PKcs localization to DSBs and interaction with Ku, thereby promoting DSB repair by NHEJ. SIRT2 deacetylase activity governs cellular resistance to DSB-inducing agents and promotes NHEJ. SIRT2 furthermore interacts with and deacetylates DNA-PKcs in response to IR. SIRT2 deacetylase activity facilitates DNA-PKcs interaction with Ku and localization to DSBs and promotes DNA-PK activation and phosphorylation of downstream NHEJ substrates. Moreover, targeting SIRT2 with AGK2, a SIRT2-specific inhibitor, augments the efficacy of IR in cancer cells and tumors. Our findings define a regulatory step for DNA-PK activation by SIRT2-mediated deacetylation, elucidating a critical upstream signaling event initiating the repair of DSBs by NHEJ. Furthermore, our data suggest that SIRT2 inhibition may be a promising rationale-driven therapeutic strategy for increasing the effectiveness of radiation therapy.","journal":"Nucleic Acids Research","year":2023,"id":328339,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":324907,"name":"Priya Kapoor-Vazirani","orcid":null,"position":1,"is_corresponding":false},{"id":354300,"name":"Ganji Purnachandra Nagaraju","orcid":"0000-0002-4989-5234","position":2,"is_corresponding":false},{"id":702048,"name":"Hui Zhang","orcid":"0000-0001-6028-2554","position":3,"is_corresponding":false},{"id":891764,"name":"Sandip Kumar Rath","orcid":"0000-0003-4589-4039","position":4,"is_corresponding":false},{"id":245014,"name":"Nho Cong Luong","orcid":"0000-0001-6625-9785","position":5,"is_corresponding":false},{"id":323940,"name":"Ramona Haji‐Seyed‐Javadi","orcid":"0000-0003-4236-4753","position":6,"is_corresponding":false},{"id":638740,"name":"Fatmata Sesay","orcid":"0000-0002-9973-3639","position":7,"is_corresponding":false},{"id":1050301,"name":"Shi-Ya Wang","orcid":null,"position":8,"is_corresponding":false},{"id":21522,"name":"Duc M. Duong","orcid":"0000-0001-5880-1888","position":9,"is_corresponding":false},{"id":891767,"name":"Waaqo Daddacha","orcid":"0000-0003-1197-0742","position":10,"is_corresponding":false},{"id":323937,"name":"Elizabeth V. Minten","orcid":"0000-0002-2078-2383","position":11,"is_corresponding":false},{"id":1050302,"name":"Boying S. Song","orcid":null,"position":12,"is_corresponding":false},{"id":891768,"name":"Diana Danelia","orcid":"0000-0001-6994-9511","position":13,"is_corresponding":false},{"id":366621,"name":"Xu Liu","orcid":"0000-0003-2252-7148","position":14,"is_corresponding":false},{"id":889132,"name":"Shuyi Li","orcid":"0000-0002-8658-155X","position":15,"is_corresponding":false},{"id":74596,"name":"Eric A. Ortlund","orcid":"0000-0001-8855-3029","position":16,"is_corresponding":false},{"id":21539,"name":"Nicholas T. Seyfried","orcid":"0000-0002-4507-624X","position":17,"is_corresponding":false},{"id":324397,"name":"David M. Smalley","orcid":"0000-0003-3239-9055","position":18,"is_corresponding":false},{"id":1049767,"name":"Ya Wang","orcid":"0000-0002-5528-2872","position":19,"is_corresponding":false},{"id":315131,"name":"Xingming Deng","orcid":"0000-0003-0319-1511","position":20,"is_corresponding":false},{"id":1049768,"name":"William S. Dynan","orcid":"0000-0002-4045-5662","position":21,"is_corresponding":false},{"id":354302,"name":"Bassel F. El‐Rayes","orcid":"0000-0002-2661-5746","position":22,"is_corresponding":false},{"id":241117,"name":"Anthony J. Davis","orcid":"0000-0003-0184-3651","position":23,"is_corresponding":false},{"id":323946,"name":"David S. Yu","orcid":"0000-0002-2781-5379","position":24,"is_corresponding":false},{"id":781897,"name":"PamelaSara E. 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