{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T14:52:18Z","timestamp":1774536738405,"version":"3.50.1"},"reference-count":59,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/01h0zpd94","doi-asserted-by":"publisher","award":["82273130"],"award-info":[{"award-number":["82273130"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes","award":["JYY2023-14"],"award-info":[{"award-number":["JYY2023-14"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cells rely heavily on DNA repair networks to survive genomic damage. For repairing double-strand breaks, Non-Homologous End Joining (NHEJ) remains the primary pathway, which is largely controlled by the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Researchers have long studied how phosphorylation drives this kinase. However, recent data point to an important additional layer of control. Drawing on evidence accumulated over the past two decades, we propose a \u201cSpatiotemporal Logic Circuit\u201d model for DNA-PKcs regulation. In this model, SUMO-associated interactions may help stabilize synaptic assembly, HUWE1-mediated neddylation may facilitate kinase activation at Lys4007, and K48-linked ubiquitination\u2014potentially involving RNF144A\u2014may contribute to the turnover of persistent repair complexes. Importantly, we frame these UBL-mediated events within the broader autophosphorylation-driven conformational cycle of DNA-PKcs, which remains central to NHEJ progression. Additionally, we highlight the structural interface where activation and degradation signals may converge and the extraction barrier posed by the massive DNA-PKcs scaffold. From a translational perspective, we argue that the exceptional size of DNA-PKcs (~470 kDa) and its topological entrapment on DNA render it an unusually challenging PROTAC target\u2014one that may require p97\/VCP-assisted extraction before proteolysis can proceed. We also highlight the underappreciated risk that E3 ligase loss-of-function, already documented in BET-PROTAC resistance, may similarly undermine DNA-PKcs degrader strategies.<\/jats:p>","DOI":"10.3390\/biom16040498","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:50:15Z","timestamp":1774533015000},"page":"498","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering the Ubiquitin-like Code of DNA-PK: Mechanisms and Therapeutic Opportunities"],"prefix":"10.3390","volume":"16","author":[{"given":"Jiaqi","family":"Zhao","sequence":"first","affiliation":[{"name":"Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhendong","family":"Qin","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiabao","family":"Hou","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingjun","family":"Lu","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingwei","family":"Guo","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinghong","family":"Wu","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenyang","family":"Wang","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyue","family":"Zhu","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8360-1543","authenticated-orcid":false,"given":"Teng","family":"Ma","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nrm.2017.48","article-title":"Non-Homologous DNA End Joining and Alternative Pathways to Double-Strand Break Repair","volume":"18","author":"Chang","year":"2017","journal-title":"Nat. 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