ArticleBritish journal of cancer2024
GCN5 mediates DNA-PKcs crotonylation for DNA double-strand break repair and determining cancer radiosensitivity.
Article in British journal of cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 18 citations in OpenAlex.
- Crotonylation of ACAT1 K181 contributes to radioresistance by impacting lactate metabolism.Communications biology · 2026Article
- GCN5 and TADA2B constitutively regulate XRCC1 function during DNA repair to maintain cell survival.Cell death and differentiation · 2026Article
- A11 Peptide Enhances Radiosensitivity by Degrading EphA2 in Nasopharyngeal Carcinoma.Cancer science · 2026Article
- Processes and therapeutic perspectives of acylation modifications of lysine and cysteine in tumors.Cell communication and signaling : CCS · 2026Review
- Protein crotonylation in cancer: mechanisms, functions, and therapeutic potential.Cell biology and toxicology · 2025Review
- Short-chain acyl post-translational modifications in cancers: Mechanisms, roles, and therapeutic implications.Cancer communications (London, England) · 2025Review
- Post-translational modifications in DNA damage repair: mechanisms underlying temozolomide resistance in glioblastoma.Oncogene · 2025Review
- High Sugar Induced RCC2 Lactylation Drives Breast Cancer Tumorigenicity Through Upregulating MAD2L1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Identification and validation of crotonylation-related diagnostic markers for lung adenocarcinoma via weighted correlation network analysis and machine learning.Translational lung cancer research · 2025Article
- Diagnostic value of a lactylation-related gene signature in hepatocellular carcinoma.Translational cancer research · 2025Article
- Novel protein acylations in ferroptosis: decoding the regulatory roles of lactylation, crotonylation, succinylation, and β-hydroxybutyrylation.Frontiers in pharmacology · 2025Review
- PARylation of GCN5 by PARP1 mediates its recruitment to DSBs and facilitates both HR and NHEJ Repair.Cellular and molecular life sciences : CMLS · 2024Article
- LINC00887 promotes GCN5-dependent H3K27cr level and CRC metastasis via recruitment of YEATS2 and enhancing ETS1 expression.Cell death & disease · 2024Article
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Authors and funding
15 authors at 5 institutions in 1 country.
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Abstract
backgroundDNA double-strand break (DSB) induction and repair are important events for determining cell survival and the outcome of cancer radiotherapy. The DNA-dependent protein kinase (DNA-PK) complex functions at the apex of DSBs repair, and its assembly and activity are strictly regulated by post-translation modifications (PTMs)-associated interactions. However, the PTMs of the catalytic subunit DNA-PKcs and how they affect DNA-PKcs's functions are not fully understood.
methodsMass spectrometry analyses were performed to identify the crotonylation sites of DNA-PKcs in response to γ-ray irradiation. Co-immunoprecipitation (Co-IP), western blotting, in vitro crotonylation assays, laser microirradiation assays, in vitro DNA binding assays, in vitro DNA-PK assembly assays and IF assays were employed to confirm the crotonylation, identify the crotonylase and decrotonylase, and elucidate how crotonylation regulates the activity and function of DNA-PKcs. Subcutaneous xenografts of human HeLa GCN5 WT or HeLa GCN5 siRNA cells in BALB/c nude mice were generated and utilized to assess tumor proliferation in vivo after radiotherapy.
resultsHere, we reveal that K525 is an important site of DNA-PKcs for crotonylation, and whose level is sharply increased by irradiation. The histone acetyltransferase GCN5 functions as the crotonylase for K525-Kcr, while HDAC3 serves as its dedicated decrotonylase. K525 crotonylation enhances DNA binding activity of DNA-PKcs, and facilitates assembly of the DNA-PK complex. Furthermore, GCN5-mediated K525 crotonylation is indispensable for DNA-PKcs autophosphorylation and the repair of double-strand breaks in the NHEJ pathway. GCN5 suppression significantly sensitizes xenograft tumors of mice to radiotherapy.
conclusionsOur study defines K525 crotonylation of DNA-PKcs is important for the DNA-PK complex assembly and DSBs repair activity via NHEJ pathway. Targeting GCN5-mediated K525 Kcr of DNA-PKcs may be a promising therapeutic strategy for improving the outcome of cancer radiotherapy.
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