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Biomolecules Nov 2020RNF11 (Ring Finger Protein 11) is a 154 amino-acid long protein that contains a RING-H2 domain, whose sequence has remained substantially unchanged throughout vertebrate... (Review)
Review
RNF11 (Ring Finger Protein 11) is a 154 amino-acid long protein that contains a RING-H2 domain, whose sequence has remained substantially unchanged throughout vertebrate evolution. RNF11 has drawn attention as a modulator of protein degradation by HECT E3 ligases. Indeed, the large number of substrates that are regulated by HECT ligases, such as ITCH, SMURF1/2, WWP1/2, and NEDD4, and their role in turning off the signaling by ubiquitin-mediated degradation, candidates RNF11 as the master regulator of a plethora of signaling pathways. Starting from the analysis of the primary sequence motifs and from the list of RNF11 protein partners, we summarize the evidence implicating RNF11 as an important player in modulating ubiquitin-regulated processes that are involved in transforming growth factor beta (TGF-β), nuclear factor-κB (NF-κB), and Epidermal Growth Factor (EGF) signaling pathways. This connection appears to be particularly significant, since RNF11 is overexpressed in several tumors, even though its role as tumor growth inhibitor or promoter is still controversial. The review highlights the different facets and peculiarities of this unconventional small RING-E3 ligase and its implication in tumorigenesis, invasion, neuroinflammation, and cancer metastasis.
Topics: Animals; DNA-Binding Proteins; Humans; Neoplasms; Proteolysis; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 33187263
DOI: 10.3390/biom10111538 -
BioEssays : News and Reviews in... Jun 2023Numerous eukaryotic DNA processing enzymes, such as DNA polymerases and ligases, bind the processivity factor PCNA, which acts as a platform to recruit and regulate the... (Review)
Review
Numerous eukaryotic DNA processing enzymes, such as DNA polymerases and ligases, bind the processivity factor PCNA, which acts as a platform to recruit and regulate the binding of enzymes to their DNA substrate. Multiple PCNA-interacting motifs (PIPs) are present in these enzymes, but their individual structural and functional role has been a matter of debate. Recent cryo-EM reconstructions of high-fidelity DNA polymerase Pol δ (Pol δ), translesion synthesis DNA polymerase κ (Pol κ) and Ligase 1 (Lig1) bound to a DNA substrate and PCNA demonstrate that the critical interaction with PCNA involves the internal PIP proximal to the catalytic domain. The ancillary PIPs, located in long disordered regions, are instead invisible in the reconstructions, and appear to function as flexible tethers when the enzymes fall off the DNA. In this review, we discuss the recent structural advancements and propose a functional hierarchy for the PIPs in Pol δ, Pol κ, and Lig1.
Topics: Proliferating Cell Nuclear Antigen; Protein Binding; DNA-Directed DNA Polymerase; DNA; DNA Replication; DNA Polymerase III
PubMed: 37039277
DOI: 10.1002/bies.202300020 -
Journal of Molecular Biology Jan 2024The joining of breaks in the DNA phosphodiester backbone is essential for genome integrity. Breaks are generated during normal processes such as DNA replication,... (Review)
Review
The joining of breaks in the DNA phosphodiester backbone is essential for genome integrity. Breaks are generated during normal processes such as DNA replication, cytosine demethylation during differentiation, gene rearrangement in the immune system and germ cell development. In addition, they are generated either directly by a DNA damaging agent or indirectly due to damage excision during repair. Breaks are joined by a DNA ligase that catalyzes phosphodiester bond formation at DNA nicks with 3' hydroxyl and 5' phosphate termini. Three human genes encode ATP-dependent DNA ligases. These enzymes have a conserved catalytic core consisting of three subdomains that encircle nicked duplex DNA during ligation. The DNA ligases are targeted to different nuclear DNA transactions by specific protein-protein interactions. Both DNA ligase IIIα and DNA ligase IV form stable complexes with DNA repair proteins, XRCC1 and XRCC4, respectively. There is functional redundancy between DNA ligase I and DNA ligase IIIα in DNA replication, excision repair and single-strand break repair. Although DNA ligase IV is a core component of the major double-strand break repair pathway, non-homologous end joining, the other enzymes participate in minor, alternative double-strand break repair pathways. In contrast to the nucleus, only DNA ligase IIIα is present in mitochondria and is essential for maintaining the mitochondrial genome. Human immunodeficiency syndromes caused by mutations in either LIG1 or LIG4 have been described. Preclinical studies with DNA ligase inhibitors have identified potentially targetable abnormalities in cancer cells and evidence that DNA ligases are potential targets for cancer therapy.
Topics: Animals; Humans; DNA; DNA Damage; DNA Ligase ATP; DNA Ligases; DNA Repair; DNA Replication; X-ray Repair Cross Complementing Protein 1
PubMed: 37714297
DOI: 10.1016/j.jmb.2023.168276 -
Nucleic Acids Research Sep 2020DNA ligases are diverse enzymes with essential functions in replication and repair of DNA; here we review recent advances in their structure and distribution and discuss... (Review)
Review
DNA ligases are diverse enzymes with essential functions in replication and repair of DNA; here we review recent advances in their structure and distribution and discuss how this contributes to understanding their biological roles and technological potential. Recent high-resolution crystal structures of DNA ligases from different organisms, including DNA-bound states and reaction intermediates, have provided considerable insight into their enzymatic mechanism and substrate interactions. All cellular organisms possess at least one DNA ligase, but many species encode multiple forms some of which are modular multifunctional enzymes. New experimental evidence for participation of DNA ligases in pathways with additional DNA modifying enzymes is defining their participation in non-redundant repair processes enabling elucidation of their biological functions. Coupled with identification of a wealth of DNA ligase sequences through genomic data, our increased appreciation of the structural diversity and phylogenetic distribution of DNA ligases has the potential to uncover new biotechnological tools and provide new treatment options for bacterial pathogens.
Topics: Catalysis; DNA Ligases; Genome; Humans; Models, Molecular; Protein Conformation; Structure-Activity Relationship
PubMed: 32365176
DOI: 10.1093/nar/gkaa307 -
International Journal of Molecular... Jan 2021X-ray analysis cannot provide quantitative estimates of the relative contribution of non-specific, specific, strong, and weak contacts of extended DNA molecules to their... (Review)
Review
X-ray analysis cannot provide quantitative estimates of the relative contribution of non-specific, specific, strong, and weak contacts of extended DNA molecules to their total affinity for enzymes and proteins. The interaction of different enzymes and proteins with long DNA and RNA at the quantitative molecular level can be successfully analyzed using the method of the stepwise increase in ligand complexity (SILC). The present review summarizes the data on stepwise increase in ligand complexity (SILC) analysis of nucleic acid recognition by various enzymes-replication, restriction, integration, topoisomerization, six different repair enzymes (uracil DNA glycosylase, Fpg protein from , human 8-oxoguanine-DNA glycosylase, human apurinic/apyrimidinic endonuclease, RecA protein, and DNA-ligase), and five DNA-recognizing proteins (RNA helicase, human lactoferrin, alfa-lactalbumin, human blood albumin, and IgGs against DNA). The relative contributions of structural elements of DNA fragments "covered" by globules of enzymes and proteins to the total affinity of DNA have been evaluated. Thermodynamic and catalytic factors providing discrimination of unspecific and specific DNAs by these enzymes on the stages of primary complex formation following changes in enzymes and DNAs or RNAs conformations and direct processing of the catalysis of the reactions were found. General regularities of recognition of nucleic acid by DNA-dependent enzymes, proteins, and antibodies were established.
Topics: Animals; Antibodies; DNA; DNA Glycosylases; DNA Helicases; DNA Ligases; DNA Topoisomerases, Type I; DNA-(Apurinic or Apyrimidinic Site) Lyase; DNA-Directed DNA Polymerase; Deoxyribonuclease EcoRI; Humans; Lactalbumin; Lactoferrin; Proteins; Rec A Recombinases; Serum Albumin, Human
PubMed: 33573045
DOI: 10.3390/ijms22031369 -
Nucleic Acids Research Apr 2021DNA methylation is essential to development and cellular physiology in mammals. Faulty DNA methylation is frequently observed in human diseases like cancer and... (Review)
Review
DNA methylation is essential to development and cellular physiology in mammals. Faulty DNA methylation is frequently observed in human diseases like cancer and neurological disorders. Molecularly, this epigenetic mark is linked to other chromatin modifications and it regulates key genomic processes, including transcription and splicing. Each round of DNA replication generates two hemi-methylated copies of the genome. These must be converted back to symmetrically methylated DNA before the next S-phase, or the mark will fade away; therefore the maintenance of DNA methylation is essential. Mechanistically, the maintenance of this epigenetic modification takes place during and after DNA replication, and occurs within the very dynamic context of chromatin re-assembly. Here, we review recent discoveries and unresolved questions regarding the mechanisms, dynamics and fidelity of DNA methylation maintenance in mammals. We also discuss how it could be regulated in normal development and misregulated in disease.
Topics: Animals; Chromatin Assembly and Disassembly; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; DNA Replication; Epigenesis, Genetic; Humans; Mammals; Neoplasms; Nervous System Diseases; Ubiquitin-Protein Ligases
PubMed: 33300031
DOI: 10.1093/nar/gkaa1154 -
Functional & Integrative Genomics Dec 2022The maintenance of epigenetic characteristics is essential for the normal growth and development of organisms. The maintenance of DNA methylation is an important way to... (Review)
Review
The maintenance of epigenetic characteristics is essential for the normal growth and development of organisms. The maintenance of DNA methylation is an important way to maintain the epigenetic characteristics of organisms. DNMT1 is a core enzyme that maintains intracellular DNA methylation, and UHRF1, as a cofactor of DNMT1, plays an important role in the regulation of DNA methylation by DNMT1. The maintenance of DNA methylation mediated by UHRF1-DNMT1 complex is involved in the regulation of many vital activities. This review describes the whole molecular process of UHRF1-DNMT1 pathway from the opening of inhibitory structure to the end of maintenance methylation in detail and lists some latest biological research progress related to this pathway in the development of early embryonic, maintenance of pluripotency of embryonic stem cells, regulation of expression of imprinted genes, inactivation of X chromosome, and development of cancer. Finally, put forward some problems remained to be solved at present and new thoughts.
Topics: DNA Methylation; DNA (Cytosine-5-)-Methyltransferases; CCAAT-Enhancer-Binding Proteins; Ubiquitin-Protein Ligases; Protein Processing, Post-Translational
PubMed: 36372834
DOI: 10.1007/s10142-022-00918-9 -
Proceedings of the Japan Academy.... 2022The UHRF protein family consists of multidomain regulatory proteins that sense modification status of DNA and/or proteins and catalyze the ubiquitylation of target... (Review)
Review
The UHRF protein family consists of multidomain regulatory proteins that sense modification status of DNA and/or proteins and catalyze the ubiquitylation of target proteins. Through their functional domains, they interact with other molecules and serve as a hub for regulatory networks of several important biological processes, including maintenance of DNA methylation and DNA damage repair. The UHRF family is conserved in vertebrates and plants but is missing from fungi and many nonvertebrate animals. Mammals commonly have UHRF1 and UHRF2, but, despite their high structural similarity, the two paralogues appear to have distinct functions. Furthermore, UHRF1 and UHRF2 show different expression patterns and different outcomes in gene knockout experiments. In this review, we summarize the current knowledge on the molecular function of the UHRF family in various biological pathways and discuss their roles in epigenetics, development, gametogenesis, and carcinogenesis, with a focus on the mammalian UHRF proteins.
Topics: Animals; CCAAT-Enhancer-Binding Proteins; Carcinogenesis; DNA; DNA Methylation; Epigenesis, Genetic; Mammals; Ubiquitin-Protein Ligases
PubMed: 36216533
DOI: 10.2183/pjab.98.021 -
Molecules (Basel, Switzerland) Feb 2023RING finger protein 168 (RNF168) is an E3 ubiquitin ligase with the RING finger domain. It is an important protein contributing to the DNA double-strand damage repair... (Review)
Review
RING finger protein 168 (RNF168) is an E3 ubiquitin ligase with the RING finger domain. It is an important protein contributing to the DNA double-strand damage repair pathway. Recent studies have found that RNF168 is significantly implicated in the occurrence and development of various cancers. Additionally, RNF168 contributes to the drug resistance of tumor cells by enhancing their DNA repair ability or regulating the degradation of target proteins. This paper summarizes and prospects the research progress of the structure and main functions of RNF168, especially its roles and the underlying mechanisms in tumorigenesis.
Topics: Humans; DNA Repair; Ubiquitin-Protein Ligases; Carcinogenesis; Ubiquitination; DNA Damage
PubMed: 36771081
DOI: 10.3390/molecules28031417 -
Nucleic Acids Research Jan 2023Double-strand DNA breaks (DSBs) are toxic to cells, and improper repair can cause chromosomal abnormalities that initiate and drive cancer progression. DNA ligases III...
Double-strand DNA breaks (DSBs) are toxic to cells, and improper repair can cause chromosomal abnormalities that initiate and drive cancer progression. DNA ligases III and IV (LIG3, LIG4) have long been credited for repair of DSBs in mammals, but recent evidence suggests that DNA ligase I (LIG1) has intrinsic end-joining (EJ) activity that can compensate for their loss. To test this model, we employed in vitro biochemical assays to compare EJ by LIG1 and LIG3. The ligases join blunt-end and 3'-overhang-containing DNA substrates with similar catalytic efficiency, but LIG1 joins 5'-overhang-containing DNA substrates ∼20-fold less efficiently than LIG3 under optimal conditions. LIG1-catalyzed EJ is compromised at a physiological concentration of Mg2+, but its activity is restored by increased molecular crowding. In contrast to LIG1, LIG3 efficiently catalyzes EJ reactions at a physiological concentration of Mg2+ with or without molecular crowding. Under all tested conditions, LIG3 has greater affinity than LIG1 for DNA ends. Remarkably, LIG3 can ligate both strands of a DSB during a single binding encounter. The weaker DNA binding affinity of LIG1 causes significant abortive ligation that is sensitive to molecular crowding and DNA terminal structure. These results provide new insights into mechanisms of alternative nonhomologous EJ.
Topics: Animals; Humans; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Ligase ATP; DNA Repair; Magnesium; Mammals
PubMed: 36625284
DOI: 10.1093/nar/gkac1263