{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUBE2F is a NEDD8‐conjugating enzyme whose activity is tightly controlled by specific molecular recognition events. Structural and biochemical studies have revealed that N-terminal acetylation of UBE2F promotes its selective recognition by DCN-like co-E3 proteins, which in turn modulate its engagement in various neddylation cascades. These interactions, dictated by the acetylated methionine and surrounding residues, ensure a distinct binding affinity compared with other E2 enzymes, thereby contributing to the fine-tuning of cullin neddylation processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of non-small cell lung cancer (NSCLC), UBE2F has been shown to be overexpressed and to predict poor patient outcomes. Functionally, UBE2F forms a complex with SAG and CUL5, thereby activating CRL5. This activation leads to the K11-linked polyubiquitylation and proteasomal degradation of NOXA, a key pro-apoptotic protein. The downregulation of NOXA confers survival and growth advantages to lung cancer cells, highlighting UBE2F's oncogenic potential in NSCLC."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther complexity in UBE2F regulation is provided by its cross-talk with UBE2M. Under stress conditions, UBE2M is upregulated via transcriptional cues and can function not only as a neddylation enzyme but also as a ubiquitylation E2. In this dual role, UBE2M mediates the ubiquitylation and subsequent degradation of UBE2F. This reduction in UBE2F levels leads to CRL5 inactivation and the accumulation of NOXA, thereby suppressing lung cancer cell growth. This negative regulatory axis underscores an additional layer of control within the neddylation network."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition, platinum-based chemotherapy has been found to affect UBE2F stability. Treatment with platinum drugs disrupts the association between UBE2F and the Cullin-Ring E3 ligase component RBX1, thereby impairing proteasomal degradation. The resulting accumulation of UBE2F enhances CUL5 neddylation and activity, which further reduces NOXA levels and diminishes apoptotic responses in lung cancer cells. Consequently, targeting UBE2F represents a promising strategy to sensitize tumors to platinum-based treatments."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these studies establish UBE2F as a pivotal regulator of neddylation cascades that modulate apoptosis, tumor growth, and treatment resistance in lung cancer. Given its multifaceted role—from molecular recognition by DCN-like proteins to orchestration of CRL5-dependent NOXA degradation and its stabilization in response to chemotherapeutic stress—the modulation of UBE2F offers a promising target for overcoming both chemotherapy and radiotherapy resistance in NSCLC, an area of great clinical significance especially in the context of emerging radiosensitization strategies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Julie K Monda, Daniel C Scott, Darcie J Miller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural conservation of distinctive N-terminal acetylation-dependent interactions across a family of mammalian NEDD8 ligation enzymes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Structure (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.str.2012.10.013"}], "href": "https://doi.org/10.1016/j.str.2012.10.013"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23201271"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23201271"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Weihua Zhou, Jie Xu, Haomin Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neddylation E2 UBE2F Promotes the Survival of Lung Cancer Cells by Activating CRL5 to Degrade NOXA via the K11 Linkage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-16-1585"}], "href": "https://doi.org/10.1158/1078-0432.CCR-16-1585"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27591266"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27591266"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Weihua Zhou, Jie Xu, Mingjia Tan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "UBE2M Is a Stress-Inducible Dual E2 for Neddylation and Ubiquitylation that Promotes Targeted Degradation of UBE2F."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2018.06.002"}], "href": "https://doi.org/10.1016/j.molcel.2018.06.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29932898"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29932898"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Lisha Zhou, Jin Zhu, Wangyang Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Induction of NEDD8-conjugating enzyme E2 UBE2F by platinum protects lung cancer cells from apoptosis and confers to platinum-insensitivity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-020-03184-4"}], "href": "https://doi.org/10.1038/s41419-020-03184-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33184273"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33184273"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Lisha Zhou, Changsheng Dong, Zhuoming Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NEDD8-conjugating enzyme E2 UBE2F confers radiation resistance by protecting lung cancer cells from apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Zhejiang Univ Sci B (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1631/jzus.B2100170"}], "href": "https://doi.org/10.1631/jzus.B2100170"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34783226"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34783226"}]}]}]}