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Open Biology Sep 2019Protein ubiquitination is of great cellular importance through its central role in processes such as degradation, DNA repair, endocytosis and inflammation. Canonical... (Review)
Review
Protein ubiquitination is of great cellular importance through its central role in processes such as degradation, DNA repair, endocytosis and inflammation. Canonical ubiquitination takes place on lysine residues, but in the past 15 years non-lysine ubiquitination on serine, threonine and cysteine has been firmly established. With the emerging importance of non-lysine ubiquitination, it is crucial to identify the responsible molecular machinery and understand the mechanistic basis for non-lysine ubiquitination. Here, we first provide an overview of the literature that has documented non-lysine ubiquitination. Informed by these examples, we then discuss the molecular mechanisms and cellular implications of non-lysine ubiquitination, and conclude by outlining open questions and future perspectives in the field.
Topics: Animals; Endoplasmic Reticulum; Humans; Lysine; Proteasome Endopeptidase Complex; Proteins; Substrate Specificity; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 31530095
DOI: 10.1098/rsob.190147 -
Genes Jan 2020DNA damage leads to genome instability by interfering with DNA replication. Cells possess several damage bypass pathways that mitigate the effects of DNA damage during... (Review)
Review
DNA damage leads to genome instability by interfering with DNA replication. Cells possess several damage bypass pathways that mitigate the effects of DNA damage during replication. These pathways include translesion synthesis and template switching. These pathways are regulated largely through post-translational modifications of proliferating cell nuclear antigen (PCNA), an essential replication accessory factor. Mono-ubiquitylation of PCNA promotes translesion synthesis, and K63-linked poly-ubiquitylation promotes template switching. This article will discuss the mechanisms of how these post-translational modifications of PCNA control these bypass pathways from a structural and biochemical perspective. We will focus on the structure and function of the E3 ubiquitin ligases Rad18 and Rad5 that facilitate the mono-ubiquitylation and poly-ubiquitylation of PCNA, respectively. We conclude by reviewing alternative ideas about how these post-translational modifications of PCNA regulate the assembly of the multi-protein complexes that promote damage bypass pathways.
Topics: DNA Damage; DNA Helicases; Fungal Proteins; Humans; Lysine; Models, Molecular; Proliferating Cell Nuclear Antigen; Protein Conformation; Protein Processing, Post-Translational; Ubiquitin-Protein Ligases; Ubiquitination; Yeasts
PubMed: 32013080
DOI: 10.3390/genes11020138 -
International Journal of Molecular... Dec 2023Ubiquitination is a post-translational modification that targets specific proteins on their lysine residues. Depending on the type of ubiquitination, this modification... (Review)
Review
Ubiquitination is a post-translational modification that targets specific proteins on their lysine residues. Depending on the type of ubiquitination, this modification ultimately regulates the stability or degradation of the targeted proteins. Ubiquitination is mediated by three different classes of enzymes: the E1 ubiquitin-activating enzymes, the E2 ubiquitin-conjugating enzymes and, most importantly, the E3 ubiquitin ligases. E3 ligases are responsible for the final step of the ubiquitin cascade, interacting directly with the target proteins. E3 ligases can also be involved in DNA repair, cell cycle regulation and response to stress; alteration in their levels can be involved in oncogenic transformation and cancer progression. Of all the six hundred E3 ligases of the human genome, only three of them are specific to the mitochondrion: MARCH5, RNF185 and MUL1. Their alterations (that reflect on the alteration of the mitochondria functions) can be related to cancer progression, as underlined by the increasing research performed in recent years on these three mitochondrial enzymes. This review will focus on the function and mechanisms of the mitochondrial E3 ubiquitin ligases, as well as their important targets, in cancer development and progression, also highlighting their potential use for cancer therapy.
Topics: Humans; Ubiquitin-Protein Ligases; Ubiquitination; Ubiquitin; Proteins; Neoplasms; Mitochondria; Ubiquitin-Conjugating Enzymes; Mitochondrial Proteins
PubMed: 38139010
DOI: 10.3390/ijms242417176 -
Biochimica Et Biophysica Acta.... May 2022Mitochondrion is a double membrane organelle that is responsible for cellular respiration and production of most of the ATP in eukaryotic cells. Mitochondrial DNA... (Review)
Review
Mitochondrion is a double membrane organelle that is responsible for cellular respiration and production of most of the ATP in eukaryotic cells. Mitochondrial DNA (mtDNA) is the genetic material carried by mitochondria, which encodes some essential subunits of respiratory complexes independent of nuclear DNA. Normally, mtDNA binds to certain proteins to form a nucleoid that is stable in mitochondria. Nevertheless, a variety of physiological or pathological stresses can cause mtDNA damage, and the accumulation of damaged mtDNA in mitochondria leads to mitochondrial dysfunction, which triggers the occurrence of mitochondrial diseases in vivo. In response to mtDNA damage, cell initiates multiple pathways including mtDNA repair, degradation, clearance and release, to recover mtDNA, and maintain mitochondrial quality and cell homeostasis. In this review, we provide our current understanding of the fate of damaged mtDNA, focus on the pathways and mechanisms of removing damaged mtDNA in the cell.
Topics: DNA Damage; DNA Repair; DNA, Mitochondrial; Extracellular Vesicles; Humans; Mitochondria; Mitochondrial Diseases; Mitophagy; Signal Transduction; Ubiquitin-Protein Ligases
PubMed: 35131372
DOI: 10.1016/j.bbamcr.2022.119233 -
Proceedings of the National Academy of... Sep 2022Cop9 signalosome (CSN) regulates the function of cullin-RING E3 ubiquitin ligases (CRLs) by deconjugating the ubiquitin-like protein NEDD8 from the cullin subunit. To...
Cop9 signalosome (CSN) regulates the function of cullin-RING E3 ubiquitin ligases (CRLs) by deconjugating the ubiquitin-like protein NEDD8 from the cullin subunit. To understand the physiological impact of CSN function on the CRL network and cell proliferation, we combined quantitative mass spectrometry and genome-wide CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens to identify factors that modulate cell viability upon inhibition of CSN by the small molecule CSN5i-3. CRL components and regulators strongly modulated the antiproliferative effects of CSN5i-3, and in addition we found two pathways involved in genome integrity, SCF-APC/C-GMNN and CUL4-SETD8, that contribute substantially to the toxicity of CSN inhibition. Our data highlight the importance of CSN-mediated NEDD8 deconjugation and adaptive exchange of CRL substrate receptors in sustaining CRL function and suggest approaches for leveraging CSN inhibition for the treatment of cancer.
Topics: Azepines; COP9 Signalosome Complex; Cell Survival; Cullin Proteins; DNA Replication; Imidazoles; NEDD8 Protein; Pyrazoles; Ubiquitin-Protein Ligases
PubMed: 36037385
DOI: 10.1073/pnas.2205608119 -
Nature Communications Nov 2020Nuclear Pore complexes (NPCs) act as docking sites to anchor particular DNA lesions facilitating DNA repair by elusive mechanisms. Using replication fork barriers in...
Nuclear Pore complexes (NPCs) act as docking sites to anchor particular DNA lesions facilitating DNA repair by elusive mechanisms. Using replication fork barriers in fission yeast, we report that relocation of arrested forks to NPCs occurred after Rad51 loading and its enzymatic activity. The E3 SUMO ligase Pli1 acts at arrested forks to safeguard integrity of nascent strands and generates poly-SUMOylation which promote relocation to NPCs but impede the resumption of DNA synthesis by homologous recombination (HR). Anchorage to NPCs allows SUMO removal by the SENP SUMO protease Ulp1 and the proteasome, promoting timely resumption of DNA synthesis. Preventing Pli1-mediated SUMO chains was sufficient to bypass the need for anchorage to NPCs and the inhibitory effect of poly-SUMOylation on HR-mediated DNA synthesis. Our work establishes a novel spatial control of Recombination-Dependent Replication (RDR) at a unique sequence that is distinct from mechanisms engaged at collapsed-forks and breaks within repeated sequences.
Topics: DNA Replication; Ligases; Nuclear Pore; Proteasome Endopeptidase Complex; Recombination, Genetic; Schizosaccharomyces; Schizosaccharomyces pombe Proteins; Small Ubiquitin-Related Modifier Proteins; Transcription, Genetic
PubMed: 33159083
DOI: 10.1038/s41467-020-19516-z -
Seminars in Cancer Biology Nov 2022Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is implicated in the control of multiple essential processes, including transcription, DNA damage repair and... (Review)
Review
Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is implicated in the control of multiple essential processes, including transcription, DNA damage repair and mitotic chromosome segregation. Accordingly, aberrant regulation of H2Bub1 can induce transcriptional reprogramming and genome instability that may promote oncogenesis. Remarkably, alterations of the ubiquitin ligases and deubiquitinating enzymes regulating H2Bub1 are emerging as ubiquitous features in cancer, further supporting the possibility that the misregulation of H2Bub1 is an underlying mechanism contributing to cancer pathogenesis. To date, aberrant H2Bub1 dynamics have been reported in multiple cancer types and are associated with transcriptional changes that promote oncogenesis in a cancer type-specific manner. Owing to the multi-functional nature of H2Bub1, misregulation of its writers and erasers may drive disease initiation and progression through additional synergistic processes. Accordingly, understanding the molecular determinants and pathogenic impacts associated with aberrant H2Bub1 regulation may reveal novel drug targets and therapeutic vulnerabilities that can be exploited to develop innovative precision medicine strategies that better combat cancer. In this review, we present the normal functions of H2Bub1 in the control of DNA-associated processes and describe the pathogenic implications associated with its misregulation in cancer. We further discuss the challenges coupled with the development of therapeutic strategies targeting H2Bub1 misregulation and expose the potential benefits of designing treatments that synergistically exploit the multiple functionalities of H2Bub1 to improve treatment selectivity and efficacy.
Topics: Humans; Histones; Ubiquitination; Neoplasms; Ubiquitin-Protein Ligases; Carcinogenesis
PubMed: 34953650
DOI: 10.1016/j.semcancer.2021.12.007 -
Experimental & Molecular Medicine Oct 2022Antitumor therapeutic strategies that fundamentally rely on the induction of DNA damage to eradicate and inhibit the growth of cancer cells are integral approaches to... (Review)
Review
Antitumor therapeutic strategies that fundamentally rely on the induction of DNA damage to eradicate and inhibit the growth of cancer cells are integral approaches to cancer therapy. Although DNA-damaging therapies advance the battle with cancer, resistance, and recurrence following treatment are common. Thus, searching for vulnerabilities that facilitate the action of DNA-damaging agents by sensitizing cancer cells is an active research area. Therefore, it is crucial to decipher the detailed molecular events involved in DNA damage responses (DDRs) to DNA-damaging agents in cancer. The tumor suppressor p53 is active at the hub of the DDR. Researchers have identified an increasing number of genes regulated by p53 transcriptional functions that have been shown to be critical direct or indirect mediators of cell fate, cell cycle regulation, and DNA repair. Posttranslational modifications (PTMs) primarily orchestrate and direct the activity of p53 in response to DNA damage. Many molecules mediating PTMs on p53 have been identified. The anticancer potential realized by targeting these molecules has been shown through experiments and clinical trials to sensitize cancer cells to DNA-damaging agents. This review briefly acknowledges the complexity of DDR pathways/networks. We specifically focus on p53 regulators, protein kinases, and E3/E4 ubiquitin ligases and their anticancer potential.
Topics: Humans; Tumor Suppressor Protein p53; DNA Damage; DNA Repair; Protein Kinases; Ubiquitin-Protein Ligases; Neoplasms
PubMed: 36207426
DOI: 10.1038/s12276-022-00863-4 -
Journal of Zhejiang University.... Jan 2021DNA is the hereditary material in humans and almost all other organisms. It is essential for maintaining accurate transmission of genetic information. In the life cycle,... (Review)
Review
DNA is the hereditary material in humans and almost all other organisms. It is essential for maintaining accurate transmission of genetic information. In the life cycle, DNA replication, cell division, or genome damage, including that caused by endogenous and exogenous agents, may cause DNA aberrations. Of all forms of DNA damage, DNA double-strand breaks (DSBs) are the most serious. If the repair function is defective, DNA damage may cause gene mutation, genome instability, and cell chromosome loss, which in turn can even lead to tumorigenesis. DNA damage can be repaired through multiple mechanisms. Homologous recombination (HR) and non-homologous end joining (NHEJ) are the two main repair mechanisms for DNA DSBs. Increasing amounts of evidence reveal that protein modifications play an essential role in DNA damage repair. Protein deubiquitination is a vital post-translational modification which removes ubiquitin molecules or polyubiquitinated chains from substrates in order to reverse the ubiquitination reaction. This review discusses the role of deubiquitinating enzymes (DUBs) in repairing DNA DSBs. Exploring the molecular mechanisms of DUB regulation in DSB repair will provide new insights to combat human diseases and develop novel therapeutic approaches.
Topics: Ataxia Telangiectasia Mutated Proteins; Checkpoint Kinase 1; Checkpoint Kinase 2; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; DNA Repair Enzymes; DNA-Binding Proteins; Deubiquitinating Enzymes; Homologous Recombination; Humans; Ubiquitin-Protein Ligases
PubMed: 33448188
DOI: 10.1631/jzus.B2000309 -
Brain : a Journal of Neurology Jul 2023Biallelic mutations in PINK1/PRKN cause recessive Parkinson's disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored...
Biallelic mutations in PINK1/PRKN cause recessive Parkinson's disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA integrity and inflammation as disease modifiers in carriers of mutations in these genes. Mitochondrial DNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson's disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mitochondrial DNA variant load (area under the curve = 0.83, CI 0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbour more heteroplasmic mitochondrial DNA variants in blood (P = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in induced pluripotent stem cell-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and post-mortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Last, the heteroplasmic mitochondrial DNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, P = 0.0074). PINK1/PRKN mutations predispose individuals to mitochondrial DNA variant accumulation in a dose- and disease-dependent manner.
Topics: Humans; DNA, Mitochondrial; Parkinson Disease; Heteroplasmy; Protein Kinases; Ubiquitin-Protein Ligases; Mutation
PubMed: 36478228
DOI: 10.1093/brain/awac464