Bioorthogonal labeling and enrichment of histone monoaminylation reveal its accumulation and regulatory function in cancer cell chromatin

Zhang, Nan; Wu, Jinghua; Hossain, Farzana; Peng, Haidong; Li, Huapeng; Gibson, Connor; Chen, Min; Zhang, Huan; Gao, Shuaixin; Zheng, Xinru; Wang, Yongdong; Zhu, Jiangjiang; Wang, Jing J.; Maze, Ian; Zheng, Qingfei

doi:10.1101/2024.03.20.586010

Cited by 3 publications

(22 citation statements)

References 36 publications

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“…1A) was synthesized (Supplementary Information) and characterized, based on the protocols reported in our previous study. 13 HCT116 cells were cultured and utilized as a model of colorectal cancer to identify dopaminylated proteins.…”

Section: Resultsmentioning

confidence: 99%

“…13 Utilizing this chemical biology tool, we found that histone dopaminylation was accumulated in tumor cells that overexpress TGM2 (e.g., colon and breast cancer cells). 13 In this research, we applied this BCN-biotin probe to modify the dopaminylated proteome in colorectal cancer (HCT116) cells via the biorthogonal reaction, SPOCQ. Therefore, 425 dopaminylated proteins were significantly enriched and identified from the experimental group.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we designed and developed a BCN-based chemical probe to label and enrich dopaminylated proteins in a biorthogonal fashion, which could be employed as a panspecific antibody to study dopaminylation. 13 Utilizing this chemical biology tool, we found that histone dopaminylation was accumulated in tumor cells that overexpress TGM2 (e.g., colon and breast cancer cells). 13 In this research, we applied this BCN-biotin probe to modify the dopaminylated proteome in colorectal cancer (HCT116) cells via the biorthogonal reaction, SPOCQ.…”

Section: Discussionmentioning

confidence: 99%

“…10 Both of these two types of PTMs have been proven to serve as hallmarks in cancer cells, and thus the corresponding regulators (i.e., DJ-1/PARK7, 11 protein arginine deiminase 4, 12 and transglutaminase 2) 10 that are overexpressed in tumors may act as promising anti-cancer targets. 13 In our previous studies, we found that the fifth amino acid residue (glutamine) of H3 (H3Q5) was a major modification site of transglutaminase 2 (TGM2)-mediated dopaminylation in colorectal tumors. 13 This stable PTM is attributed to the isopeptide formation between H3Q5 and dopamine through the transamination reaction catalyzed by TGM2, which is overexpressed in colorectal cancer cells.…”

Section: Introductionmentioning

confidence: 98%

“…Recently, we have development a bicyclononyne (BCN)-containing probe that can modify and enrich dopaminylated histone proteins in a bioorthogonal manner. 13 This BCN probe with a biotin tag enabled us to conduct the chemical proteomic profiling of protein dopaminylation in cells.…”

Section: Introductionmentioning

confidence: 99%

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Chemical proteomic profiling of protein dopaminylation in colorectal cancer cells

Zhang,

Gao,

Peng

et al. 2024

Preprint

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Histone dopaminylation is a newly identified epigenetic mark that plays a role in the regulation of gene transcription, where an isopeptide bond is formed between the fifth amino acid residue of H3 (i.e., glutamine) and dopamine. In our previous studies, we discovered that the dynamics of this post-translational modification (including installation, removal, and replacement) were regulated by a single enzyme, transglutaminase 2 (TGM2), through reversible transamination. Recently, we developed a chemical probe to specifically label and enrich histone dopaminylation via bioorthogonal chemistry. Given this powerful tool, we found that histone H3 glutamine 5 dopaminylation (H3Q5dop) was highly enriched in colorectal tumors, which could be attributed to the high expression level of TGM2 in colon cancer cells. Due to the enzyme promiscuity of TGM2, non-histone proteins have also been identified as targets of dopaminylation on glutamine residues, however, the dopaminylated proteome in cancer cells still remains elusive. Here, we utilized our chemical probe to enrich dopaminylated proteins from colorectal cancer cells in a bioorthogonal manner and performed the chemical proteomics analysis. Therefore, 425 dopaminylated proteins were identified, many of which are involved in nucleic acid metabolism and transcription pathways. More importantly, a number of modification sites of these dopaminylated proteins were identified, attributed to the successful application of our chemical probe. Overall, these findings shed light on the significant association between cellular protein dopaminylation and cancer development, further suggesting that to block the installation of protein dopaminylation may become a promising anti-cancer strategy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Chemical proteomic profiling of protein dopaminylation in colorectal cancer cells

Zhang,

Gao,

Peng

et al. 2024

Preprint

Self Cite

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pH-Controlled chemoselective rapid azo-coupling reaction (CRACR) enables global profiling of serotonylation proteome in cancer cells

Zhang,

Wu,

Gao

et al. 2024

Preprint

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Serotonylation has been identified as a novel protein post-translational modification (PTM) for decades, where an isopeptide bond is formed between the glutamine residue and serotonin through transamination. Transglutaminase 2 (also known as TGM2 or TGase2) was proven to act as the main writer enzyme for this PTM and a number of key regulatory proteins (including small GTPases, fibronectin, fibrinogen, serotonin transporter, and histone H3) have been characterized as the substrates of serotonylation. However, due to the lack of pan-specific antibody for serotonylated glutamine, the precise enrichment and proteomic profiling of serotonylation still remain challenging. In our previous research, we developed an aryldiazonium probe to label protein serotonylation in a bioorthogonal manner. This chemical biology tool can be utilized alternatively for the antibody-free enrichment of serotonylated proteins, which depends on a pH-controlled chemoselective rapid azo-coupling reaction (CRACR). Here, we report the application of a photoactive aryldiazonium-biotin probe for the global profiling of serotonylation proteome in cancer cells. Thus, over 500 serotonylated proteins were identified from HCT 116 cells. Importantly, a number of modification sites of these serotonylated proteins were determine, attributed to the successful application of our chemical proteomic approach. Overall, these findings provided new insights into the significant association between cellular protein serotonylation and cancer development, further suggesting that to target TGM2-mediated monoaminylation may serve as a promising strategy for cancer therapeutics.

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Hippocampal γCaMKII dopaminylation promotes synaptic-to-nuclear signaling and memory formation

Stewart,

Fulton,

Durand-de Cuttoli

et al. 2024

Preprint

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Protein monoaminylation is a class of posttranslational modification (PTM) that contributes to transcription, physiology and behavior. While recent analyses have focused on histones as critical substrates of monoaminylation, the broader repertoire of monoaminylated proteins in brain remains unclear. Here, we report the development/implementation of a chemical probe for the biorthogonal labeling, enrichment and proteomics-based detection of dopaminylated proteins in brain. We identified 1,557 dopaminylated proteins - many synaptic - including γCaMKII, which mediates Ca2+-dependent cellular signaling and hippocampal-dependent memory. We found that γCaMKII dopaminylation is largely synaptic and mediates synaptic-to-nuclear signaling, neuronal gene expression and intrinsic excitability, and contextual memory. These results indicate a critical role for synaptic dopaminylation in adaptive brain plasticity, and may suggest roles for these phenomena in pathologies associated with altered monoaminergic signaling.

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Bioorthogonal labeling and enrichment of histone monoaminylation reveal its accumulation and regulatory function in cancer cell chromatin

Cited by 3 publications

References 36 publications

Chemical proteomic profiling of protein dopaminylation in colorectal cancer cells

Chemical proteomic profiling of protein dopaminylation in colorectal cancer cells

pH-Controlled chemoselective rapid azo-coupling reaction (CRACR) enables global profiling of serotonylation proteome in cancer cells

Hippocampal γCaMKII dopaminylation promotes synaptic-to-nuclear signaling and memory formation

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