Lysine Crotonylation: An Emerging Player in DNA Damage Response

Zhao, Yu-Qin; Hao, Shuailin; Wu, Wenchi; Li, Youhang; Hou, Kaiping; Liu, Yu; Cui, Wei; Xu, Xingzhi; Wang, Hailong

doi:10.3390/biom12101428

Cited by 7 publications

(4 citation statements)

References 98 publications

(122 reference statements)

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“…Protein crotonylation is emerging as an important player in the regulation of DNA damage signal transduction. Crotonylation generally regulates the functions of DNA repair proteins by modulating protein-protein interactions and DNA binding activities [ 54 ]. For example, RPA1 crotonylation promotes its ssDNA binding ability to facilitating RPA1 recruitment to sites of DNA damage and HR repair [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

GCN5 mediates DNA-PKcs crotonylation for DNA double-strand break repair and determining cancer radiosensitivity

Han,

Zhao,

et al. 2024

Br J Cancer

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Background DNA 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. Methods Mass 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. Results Here, 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. Conclusions Our 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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Section: Discussionmentioning

confidence: 99%

GCN5 mediates DNA-PKcs crotonylation for DNA double-strand break repair and determining cancer radiosensitivity

Han,

Zhao,

et al. 2024

Br J Cancer

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“…Lysine crotonylation (Kcr) is an emerging PTM correlated widely to transcriptional silencing, DSB repair, and DNA replication stress response, the level of which is altered by DNA damage and replication stress [205]. For example, Kcr levels of a series of DSB repair proteins such as RPA1, POLD1, and XRCC5 are upregulated prominently after DNA damage.…”

Section: Dna Damage Repair Modulated By Other Ptmsmentioning

confidence: 99%

Drug Discovery Targeting Post-Translational Modifications in Response to DNA Damages Induced by Space Radiation

Xie

Zhou

2023

IJMS

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DNA damage in astronauts induced by cosmic radiation poses a major barrier to human space exploration. Cellular responses and repair of the most lethal DNA double-strand breaks (DSBs) are crucial for genomic integrity and cell survival. Post-translational modifications (PTMs), including phosphorylation, ubiquitylation, and SUMOylation, are among the regulatory factors modulating a delicate balance and choice between predominant DSB repair pathways, such as non-homologous end joining (NHEJ) and homologous recombination (HR). In this review, we focused on the engagement of proteins in the DNA damage response (DDR) modulated by phosphorylation and ubiquitylation, including ATM, DNA-PKcs, CtIP, MDM2, and ubiquitin ligases. The involvement and function of acetylation, methylation, PARylation, and their essential proteins were also investigated, providing a repository of candidate targets for DDR regulators. However, there is a lack of radioprotectors in spite of their consideration in the discovery of radiosensitizers. We proposed new perspectives for the research and development of future agents against space radiation by the systematic integration and utilization of evolutionary strategies, including multi-omics analyses, rational computing methods, drug repositioning, and combinations of drugs and targets, which may facilitate the use of radioprotectors in practical applications in human space exploration to combat fatal radiation hazards.

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“…Accumulating evidence connects this histone mark with proliferation, DNA damage and ageing-associated mechanisms [ 97 – 100 ]. Histone Kcr were found dysregulated in several cancers, including, stomach, liver, kidney, thyroid, esophagus, colon, pancreas and lung carcinomas [ 97 , 98 ]. In hepatocellular carcinoma (HCC), it was found that high levels of Kcr, induced by the siRNA interference of histone deacetylases (HDACs) or HDAC inhibitors, decrease cancer cell motility and proliferation [ 101 ].…”

Section: Targeting Histone Non-enzymatic Covalent Modificationsmentioning

confidence: 99%

Epigenetic meets metabolism: novel vulnerabilities to fight cancer

Scumaci,

Zheng

2023

Cell Commun Signal

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Histones undergo a plethora of post-translational modifications (PTMs) that regulate nucleosome and chromatin dynamics and thus dictate cell fate. Several evidences suggest that the accumulation of epigenetic alterations is one of the key driving forces triggering aberrant cellular proliferation, invasion, metastasis and chemoresistance pathways. Recently a novel class of histone “non-enzymatic covalent modifications” (NECMs), correlating epigenome landscape and metabolic rewiring, have been described. These modifications are tightly related to cell metabolic fitness and are able to impair chromatin architecture. During metabolic reprogramming, the high metabolic flux induces the accumulation of metabolic intermediate and/or by-products able to react with histone tails altering epigenome homeostasis. The accumulation of histone NECMs is a damaging condition that cancer cells counteracts by overexpressing peculiar “eraser” enzymes capable of removing these modifications preserving histones architecture. In this review we explored the well-established NECMs, emphasizing the role of their corresponding eraser enzymes. Additionally, we provide a parterre of drugs aiming to target those eraser enzymes with the intent to propose novel routes of personalized medicine based on the identification of epi-biomarkers which might be selectively targeted for therapy.

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Lysine Crotonylation: An Emerging Player in DNA Damage Response

Cited by 7 publications

References 98 publications

GCN5 mediates DNA-PKcs crotonylation for DNA double-strand break repair and determining cancer radiosensitivity

GCN5 mediates DNA-PKcs crotonylation for DNA double-strand break repair and determining cancer radiosensitivity

Drug Discovery Targeting Post-Translational Modifications in Response to DNA Damages Induced by Space Radiation

Epigenetic meets metabolism: novel vulnerabilities to fight cancer

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