The CYLD–PARP1 feedback loop regulates DNA damage repair and chemosensitivity in breast cancer cells DOI Creative Commons
Miaomiao Zheng, Shuo Wang,

Ke-Xin Tang

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 122(1)

Published: Dec. 31, 2024

Poly(ADP-ribose) polymerase 1 (PARP1) plays a crucial role in DNA repair and genomic stability maintenance. However, the regulatory mechanisms governing PARP1 activity, particularly through deubiquitination, remain poorly elucidated. Using deubiquitinase (DUB) library binding screen, we identified cylindromatosis (CYLD) as bona fide DUB for breast cancer cells. Mechanistically, CYLD is recruited by to lesions upon genotoxic stress, where it cleaves K63-linked polyubiquitin chains on at residues K748, K940, K949, resulting compromised activation. In reciprocal manner, PARylates sites E191, E231, E259, E509, thereby enhancing its activity. Consequently, depletion of leads increased efficiency base excision confers cells with resistance alkylating agents. Conversely, overexpression enhances sensitivity PARP inhibitors (PARPi) even homologous recombination-proficient These findings offer unique insights into intricate interplay between repair, underscoring pivotal targeting this axis chemotherapy.

Language: Английский

The Emerging Role of Ubiquitin-Specific Protease 36 (USP36) in Cancer and Beyond DOI Creative Commons

Meng-Yao Niu,

Y. Liu, Jinjin Shi

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(5), P. 572 - 572

Published: May 12, 2024

The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability maintenance cellular homeostasis. deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member USP family, plays crucial role this dynamic equilibrium by hydrolyzing removing ubiquitin chains from target proteins facilitating their proteasome-dependent degradation. multifaceted functions USP36 have been implicated various disease processes, including cancer, infections, inflammation, via modulation numerous events, gene transcription regulation, cell cycle immune responses, signal transduction, tumor growth, inflammatory processes. objective review to provide comprehensive summary current state research on roles different pathological conditions. By synthesizing findings previous studies, we aimed increase our understanding mechanisms underlying these diseases identify potential therapeutic targets for treatment.

Language: Английский

Citations

4
Cardiotoxicity of Chemotherapy: A Multi-OMIC Perspective DOI Creative Commons
Yan Ma, Mandy O. J. Grootaert, Raj Nayan Sewduth

et al.

Journal of Xenobiotics, Journal Year: 2025, Volume and Issue: 15(1), P. 9 - 9

Published: Jan. 8, 2025

Chemotherapy-induced cardiotoxicity is a critical issue in cardio-oncology, as cancer treatments often lead to severe cardiovascular complications. Approximately 10% of patients succumb problems, with lung frequently experiencing arrhythmias, cardiac failure, tamponade, and metastasis. The cardiotoxic effects anti-cancer manifest at both cellular tissue levels, causing deformation cardiomyocytes, leading contractility issues fibrosis. Repeated irradiation chemotherapy increase the risk valvular, pericardial, or myocardial diseases. Multi-OMICs analyses reveal that targeting specific pathways well protein modifications, such ubiquitination phosphorylation, could offer potential therapeutic alternatives current treatments, including Angiotensin converting enzymes (ACE) inhibitors beta-blockers mitigate symptoms but do not prevent cardiomyocyte death, highlighting need for more effective therapies manage defects survivors. This review explores xenobiotic nature agents their impact on health, aiming identify novel biomarkers targets cardiotoxicity.

Language: Английский

Citations

0
Ubiquitin-specific protease: an emerging key player in cardiomyopathy DOI Creative Commons
Danlei Li, Qilin Ma

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 18, 2025

Protein quality control (PQC) plays a vital role in maintaining normal heart function, as cardiomyocytes are relatively sensitive to misfolded or damaged proteins, which tend accumulate under pathological conditions. Ubiquitin-specific protease (USP) is the largest deubiquitinating enzyme family and key component of ubiquitin proteasome system (UPS), non-lysosomal protein degradation machinery mediate PQC cells. USPs regulate stability activity target proteins that involve intracellular signaling, transcriptional inflammation, antioxidation, cell growth. Recent studies demonstrate can fibrosis, lipid metabolism, glucose homeostasis, hypertrophic response, post-ischemic recovery death such apoptosis ferroptosis cardiomyocytes. Since myocardial loss an important cardiomyopathy, therefore, these findings suggest UPSs play emerging roles cardiomyopathy. This review briefly summarizes recent literature on regulatory occurrence development giving us new insights into molecular mechanisms different cardiomyopathy potential preventive strategies for

Language: Английский

Citations

0
Deubiquitinase USP13 alleviates doxorubicin-induced cardiotoxicity through promoting the autophagy-mediated degradation of STING DOI Creative Commons
Liming Lin, Jibo Han,

Diyun Xu

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
USP20 mitigates doxorubicin-induced cardiotoxicity by deubiquitinating and stabilizing HuR DOI
Zhouqing Huang, Yunxuan Chen, S S Wu

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Abstract Background The severe cardiotoxicity of doxorubicin (Dox) significantly restricts its clinical application. Deubiquitinating enzymes (DUBs) play pivotal roles in cardiac pathophysiology because their precise regulation protein function, localization and degradation.Objectives objective this study was to investigate the role molecular mechanism ubiquitin-specific peptidase 20 (USP20), a DUB, doxorubicin-induced cardiotoxicity.Methods Cardiomyocyte-specific USP20-knockout (USP20-CKO) mice were utilized assess USP20 cardiomyopathy (DIC). Coimmunoprecipitation (co-IP) combined with liquid chromatography‒mass spectrometry/mass spectrometry (LC‒MS/MS) analysis employed screen substrate USP20. Furthermore, mutant plasmids constructed elucidate underlying human antigen R (HuR) by Finally, an AAV9 vector used overexpress hearts cardiac-specific HuR-knockout interaction between HuR.Results results revealed decrease expression Dox-stimulated mouse cardiomyocytes. knockout resulted increased cardiomyocyte ferroptosis led DIC. Mechanistically, directly interacted HuR through protease structural domain. Deubiquitination at position 154 crucial for maintaining stability cleaving K48 ubiquitin chains inhibiting proteasomal degradation. Additionally, bound GPX4 mRNA suppress degradation, thereby mitigating contributing alleviating targeted overexpression via cardiomyocytes alleviated However, cardiomyocyte-specific knockout, no longer had anti-DIC effect, indicating that HuR, as downstream target USP20, plays irreplaceable DIC.Conclusions Our findings indicate enhances deubiquitination,

Language: Английский

Citations

0
The role of deubiquitinases in cardiovascular diseases: mechanisms and therapeutic implications DOI Creative Commons

Xiaojun Fei,

Chao Song, Jian Cui

et al.

Frontiers in Cardiovascular Medicine, Journal Year: 2025, Volume and Issue: 12

Published: May 1, 2025

Cardiovascular diseases (CVDs) have become the leading cause of death globally, surpassing infectious and other chronic illnesses. The incidence mortality rates CVDs are rising worldwide, posing a key challenge in public health. ubiquitination system is vast complex. It an important post-translational modification that plays crucial role various cellular processes. Deubiquitination catalyzed by deubiquitinases (DUBs), which remove ubiquitin (Ub) from ubiquitinated proteins, thereby reversing process. DUBs play many biological processes, such as DNA repair, cell metabolism, differentiation, epigenetic regulation, protein stability control. They also participate regulation signaling pathways associated with development progression CVDs. In this review, we primarily focus on pathological mechanisms atherosclerosis (AS), foam formation, vascular remodeling (VR), endothelial-to-mesenchymal transition (End-MT), clonal hematopoiesis (CH). heart, summarize involvement including heart failure (HF), myocardial infarction (MI), hypertrophy (MH) ischemia/reperfusion (I/R) injury. Additionally, explore diabetic cardiomyopathy (DCM) use doxorubicin-induced cardiotoxicity clinical settings. A comprehensive understanding deubiquitination may provide new insights for treatment drug design

Language: Английский

Citations

0
USP36 promotes tumorigenesis and tamoxifen resistance in breast cancer by deubiquitinating and stabilizing ERα DOI Creative Commons

Ting Ting Zhuang,

Shuqing Zhang, Dongyi Liu

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: Aug. 31, 2024

Abstract Background Breast cancer is the most prevalent in women globally. Over-activated estrogen receptor (ER) α signaling considered main factor luminal breast cancers, which can be effectively managed with selective modulators (SERMs) like tamoxifen. However, approximately 30–40% of ER + cases are recurrent after tamoxifen therapy. This implies that treatment still hindered by resistance to Recent studies have suggested post-translational modifications ERα play a significant role endocrine resistance. The stability both protein and its transcriptome regulated balance between E3 ubiquitin ligases deubiquitinases. According current knowledge, 100 deubiquitinases encoded human genome, but it remains unclear critical Thus, decoding key significantly impact signaling, including control expression stability, for improvement therapeutics. Methods We used several positive cell lines, DUB siRNA library screening, xenograft models, endocrine-resistant (ERα-Y537S) model performed immunoblotting, real time PCR, RNA sequencing, immunofluorescence, luciferase activity assay investigate function USP36 progression Results In this study, we identify Ubiquitin-specific peptidase 36 (USP36) as deubiquitinase involved advancement screening. vitro vivo showed USP36, not catalytically inactive mutant (C131A), could promote through signaling. Conversely, silencing inhibited tumorigenesis. models resistant therapy, destabilized form (Y537S) restored sensitivity Molecular indicated K48-linked polyubiquitination enhanced transcriptome. It interesting note our results suggest novel biomarker cancer. Conclusion Our study revealed possibility inhibiting combined provide potential therapy

Language: Английский

Citations

2
Cardiomyocyte-specific knockout of ADAM17 alleviates doxorubicin-induced cardiomyopathy via inhibiting TNFα–TRAF3–TAK1–MAPK axis DOI Creative Commons
Lin Xie, Fei Xue,

Cheng Cheng

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 16, 2024

The pathogenesis of doxorubicin-induced cardiomyopathy remains unclear. This study was carried out to test our hypothesis that ADAM17 aggravates cardiomyocyte apoptosis induced by doxorubicin and inhibition may ameliorate cardiomyopathy. C57BL/6J mice were intraperitoneally injected with a cumulative dose induce Cardiomyocyte-specific ADAM17-knockout (A17

Language: Английский

Citations

2
USP14 Modulates Cell Pyroptosis and Ameliorates Doxorubicin-Induced Cardiotoxicity by Deubiquitinating and Stabilizing SIRT3 DOI

Zhiming Zhang,

Binwei Jin,

Yang Zhang

et al.

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 225, P. 741 - 757

Published: Oct. 30, 2024

Language: Английский

Citations

1
The CYLD–PARP1 feedback loop regulates DNA damage repair and chemosensitivity in breast cancer cells DOI Creative Commons
Miaomiao Zheng, Shuo Wang,

Ke-Xin Tang

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 122(1)

Published: Dec. 31, 2024

Poly(ADP-ribose) polymerase 1 (PARP1) plays a crucial role in DNA repair and genomic stability maintenance. However, the regulatory mechanisms governing PARP1 activity, particularly through deubiquitination, remain poorly elucidated. Using deubiquitinase (DUB) library binding screen, we identified cylindromatosis (CYLD) as bona fide DUB for breast cancer cells. Mechanistically, CYLD is recruited by to lesions upon genotoxic stress, where it cleaves K63-linked polyubiquitin chains on at residues K748, K940, K949, resulting compromised activation. In reciprocal manner, PARylates sites E191, E231, E259, E509, thereby enhancing its activity. Consequently, depletion of leads increased efficiency base excision confers cells with resistance alkylating agents. Conversely, overexpression enhances sensitivity PARP inhibitors (PARPi) even homologous recombination-proficient These findings offer unique insights into intricate interplay between repair, underscoring pivotal targeting this axis chemotherapy.

Language: Английский

Citations

0