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Current Issues in Molecular Biology 2020Ubiquitin and ubiquitin-like modifiers, such as SUMO, exert distinct physiological functions by conjugating to protein substrates. Ubiquitination or SUMOylation of... (Review)
Review
Ubiquitin and ubiquitin-like modifiers, such as SUMO, exert distinct physiological functions by conjugating to protein substrates. Ubiquitination or SUMOylation of protein substrates determine the fate of modified proteins, including proteasomal degradation, cellular re-localization, alternations in binding partners and serving as a protein-binding platform, in a ubiquitin or SUMO linkage-dependent manner. DNA damage occurs constantly in living organisms but is also repaired by distinct tightly controlled mechanisms including homologous recombination, non-homologous end joining, inter-strand crosslink repair, nucleotide excision repair and base excision repair. On sensing damaged DNA, a ubiquitination/SUMOylation landscape is established to recruit DNA damage repair factors. Meanwhile, misloaded and mission-completed repair factors will be turned over by ubiquitin or SUMO modifications as well. These ubiquitination and SUMOylation events are tightly controlled by both E3 ubiquitin/SUMO ligases and deubiquitinases/deSUMOylases. In this review, we will summarize identified ubiquitin and SUMO-related modifications and their function in distinct DNA damage repair pathways, and provide evidence for responsible E3 ligases, deubiquitinases, SUMOylases and deSUMOylases in these processes. Given that genome instability leads to human disorders including cancer, understanding detailed molecular mechanisms for ubiquitin and SUMO-related regulations in DNA damage response may provide novel insights into therapeutic modalities to treat human diseases associated with deregulated DNA damage response.
Topics: DNA Damage; DNA End-Joining Repair; DNA Repair; Homologous Recombination; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 31422933
DOI: 10.21775/cimb.035.059 -
International Journal of Biological... 2022BRCA1 is frequently down-regulated in breast cancer, the underlying mechanism is unclear. Here we identified DCAF8L1, an X-linked gene product, as a DDB1-Cullin...
BRCA1 is frequently down-regulated in breast cancer, the underlying mechanism is unclear. Here we identified DCAF8L1, an X-linked gene product, as a DDB1-Cullin associated Factor (DCAF) for CUL4 E3 ligases to target BRCA1 and BARD1 for proteasomal degradation. Forced expression of DCAF8L1 caused reduction of BRCA1 and BARD1, and impaired DNA damage repair function, conferring increased sensitivity to irradiation and DNA damaging agents, as well as Olaparib, a PARPi anticancer drug; while depletion of DCAF8L1 restored BRCA1 and suppressed the growth of its xenograft tumors. Furthermore, the expression of DCAF8L1 was induced in human H9 ES cells during transition from primed to naïve state when Xi chromosome was reactivated. Aberrant expression of DCAF8L1 was observed in human breast fibroadenoma and breast cancer. These findings suggest that CRL4 is an important E3 ligase that may participate in the development of breast cancer, probably through regulating the stability of BRCA1 and BARD1 tumor suppressor, linking BRCA1 and X chromosome inactivation to breast carcinogenesis.
Topics: BRCA1 Protein; Breast Neoplasms; DNA Repair; Female; Humans; Protein Stability; Receptors, Interleukin-17; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases
PubMed: 35280675
DOI: 10.7150/ijbs.57178 -
International Journal of Molecular... May 2021Small ubiquitin-like modifier (SUMO)-targeted E3 ubiquitin ligases (STUbLs) are specialized enzymes that recognize SUMOylated proteins and attach ubiquitin to them. They... (Review)
Review
Small ubiquitin-like modifier (SUMO)-targeted E3 ubiquitin ligases (STUbLs) are specialized enzymes that recognize SUMOylated proteins and attach ubiquitin to them. They therefore connect the cellular SUMOylation and ubiquitination circuits. STUbLs participate in diverse molecular processes that span cell cycle regulated events, including DNA repair, replication, mitosis, and transcription. They operate during unperturbed conditions and in response to challenges, such as genotoxic stress. These E3 ubiquitin ligases modify their target substrates by catalyzing ubiquitin chains that form different linkages, resulting in proteolytic or non-proteolytic outcomes. Often, STUbLs function in compartmentalized environments, such as the nuclear envelope or kinetochore, and actively aid in nuclear relocalization of damaged DNA and stalled replication forks to promote DNA repair or fork restart. Furthermore, STUbLs reside in the same vicinity as SUMO proteases and deubiquitinases (DUBs), providing spatiotemporal control of their targets. In this review, we focus on the molecular mechanisms by which STUbLs help to maintain genome stability across different species.
Topics: Animals; DNA Repair; Genomic Instability; Humans; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 34065507
DOI: 10.3390/ijms22105391 -
International Journal of Molecular... Mar 2022Small ubiquitin-like modifier (SUMO)ylation is a reversible post-translational modification that plays a crucial role in numerous aspects of cell physiology, including... (Review)
Review
Small ubiquitin-like modifier (SUMO)ylation is a reversible post-translational modification that plays a crucial role in numerous aspects of cell physiology, including cell cycle regulation, DNA damage repair, and protein trafficking and turnover, which are of importance for cell homeostasis. Mechanistically, SUMOylation is a sequential multi-enzymatic process where SUMO E3 ligases recruit substrates and accelerate the transfer of SUMO onto targets, modulating their interactions, localization, activity, or stability. Accumulating evidence highlights the critical role of dysregulated SUMO E3 ligases in processes associated with the occurrence and development of cancers. In the present review, we summarize the SUMO E3 ligases, in particular, the novel ones recently identified, and discuss their regulatory roles in cancer pathogenesis.
Topics: Humans; Ligases; Neoplasms; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 35408996
DOI: 10.3390/ijms23073639 -
Nucleic Acids Research Jun 2021During S phase, the cooperation between the macromolecular complexes regulating DNA synthesis, epigenetic information maintenance and DNA repair is advantageous for... (Review)
Review
During S phase, the cooperation between the macromolecular complexes regulating DNA synthesis, epigenetic information maintenance and DNA repair is advantageous for cells, as they can rapidly detect DNA damage and initiate the DNA damage response (DDR). UHRF1 is a fundamental epigenetic regulator; its ability to coordinate DNA methylation and histone code is unique across proteomes of different species. Recently, UHRF1's role in DNA damage repair has been explored and recognized to be as important as its role in maintaining the epigenome. UHRF1 is a sensor for interstrand crosslinks and a determinant for the switch towards homologous recombination in the repair of double-strand breaks; its loss results in enhanced sensitivity to DNA damage. These functions are finely regulated by specific post-translational modifications and are mediated by the SRA domain, which binds to damaged DNA, and the RING domain. Here, we review recent studies on the role of UHRF1 in DDR focusing on how it recognizes DNA damage and cooperates with other proteins in its repair. We then discuss how UHRF1's epigenetic abilities in reading and writing histone modifications, or its interactions with ncRNAs, could interlace with its role in DDR.
Topics: Animals; CCAAT-Enhancer-Binding Proteins; DNA Damage; DNA Repair; Epigenesis, Genetic; Epigenome; Genomic Instability; Histone Code; Humans; Ubiquitin-Protein Ligases
PubMed: 33939809
DOI: 10.1093/nar/gkab293 -
Critical Reviews in Analytical Chemistry 2023DNA biosensors play important roles in environmental, medical, industrial and agricultural analysis. Many DNA biosensors have been designed based on the enzyme catalytic... (Review)
Review
DNA biosensors play important roles in environmental, medical, industrial and agricultural analysis. Many DNA biosensors have been designed based on the enzyme catalytic reaction. Because of the importance of enzymes in biosensors, we present a review on this topic. In this review, the enzymes were divided into DNAzymes and nucleases according to their chemical nature. Firstly, we introduced the DNAzymes with different function inducing cleavage, metalation, peroxidase, ligation and allosterism. In this section, the G-quadruplex DNAzyme, as a hot topic in recent years, was described in detail. Then, the nucleases-assisted signal amplification method was also reviewed in three categories including exonucleases, endonucleases and other nucleases according to the digestion sites in DNA substrates. In exonucleases section, the Exo I and Exo III were selected as examples. Then, the DNase I, BamH I, nicking endonuclease, S1 nuclease, the duplex specific nuclease (DSN) and RNases were chosen to illustrate the application of endonucleases. In other nucleases section, DNA polymerases and DNA ligases were detailed. Last, the challenges and future perspectives in the field were discussed.
Topics: DNA, Catalytic; DNA; Biosensing Techniques; Endonucleases
PubMed: 34225516
DOI: 10.1080/10408347.2021.1944046 -
Trends in Cell Biology Feb 2021In preparation for cell division, the genome must be copied with high fidelity. However, replisomes often encounter obstacles, including bulky DNA lesions caused by... (Review)
Review
In preparation for cell division, the genome must be copied with high fidelity. However, replisomes often encounter obstacles, including bulky DNA lesions caused by reactive metabolites and chemotherapeutics, as well as stable nucleoprotein complexes. Here, we discuss recent advances in our understanding of TRAIP, a replisome-associated E3 ubiquitin ligase that is mutated in microcephalic primordial dwarfism. In interphase, TRAIP helps replisomes overcome DNA interstrand crosslinks and DNA-protein crosslinks, whereas in mitosis it triggers disassembly of all replisomes that remain on chromatin. We describe a model to explain how TRAIP performs these disparate functions and how they help maintain genome integrity.
Topics: Animals; DNA Helicases; DNA Repair; DNA Replication; Humans; Mitosis; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination; Xenopus laevis
PubMed: 33317933
DOI: 10.1016/j.tcb.2020.11.007 -
Nature Communications Nov 2019DNA ligases catalyze the joining of DNA strands to complete DNA replication, recombination and repair transactions. To protect the integrity of the genome, DNA ligase 1...
DNA ligases catalyze the joining of DNA strands to complete DNA replication, recombination and repair transactions. To protect the integrity of the genome, DNA ligase 1 (LIG1) discriminates against DNA junctions harboring mutagenic 3'-DNA mismatches or oxidative DNA damage, but how such high-fidelity ligation is enforced is unknown. Here, X-ray structures and kinetic analyses of LIG1 complexes with undamaged and oxidatively damaged DNA unveil that LIG1 employs Mg-reinforced DNA binding to validate DNA base pairing during the adenylyl transfer and nick-sealing ligation reaction steps. Our results support a model whereby LIG1 fidelity is governed by a high-fidelity (HiFi) interface between LIG1, Mg, and the DNA substrate that tunes the enzyme to release pro-mutagenic DNA nicks. In a second tier of protection, LIG1 activity is surveilled by Aprataxin (APTX), which suppresses mutagenic and abortive ligation at sites of oxidative DNA damage.
Topics: DNA; DNA Breaks, Single-Stranded; DNA Damage; DNA Ligase ATP; DNA Repair; DNA Replication; DNA-Binding Proteins; Guanine; Humans; Magnesium; Nuclear Proteins; Nucleic Acid Conformation; Oxidation-Reduction; Protein Structure, Tertiary; Recombinational DNA Repair
PubMed: 31780661
DOI: 10.1038/s41467-019-13478-7 -
Cell Reports Mar 2021The breast cancer type I susceptibility protein (BRCA1) and BRCA1-associated RING domain protein I (BARD1) heterodimer promote genome integrity through pleiotropic...
The breast cancer type I susceptibility protein (BRCA1) and BRCA1-associated RING domain protein I (BARD1) heterodimer promote genome integrity through pleiotropic functions, including DNA double-strand break (DSB) repair by homologous recombination (HR). BRCA1-BARD1 heterodimerization is required for their mutual stability, HR function, and role in tumor suppression; however, the upstream signaling events governing BRCA1-BARD1 heterodimerization are unclear. Here, we show that SIRT2, a sirtuin deacetylase and breast tumor suppressor, promotes BRCA1-BARD1 heterodimerization through deacetylation. SIRT2 complexes with BRCA1-BARD1 and deacetylates conserved lysines in the BARD1 RING domain, interfacing BRCA1, which promotes BRCA1-BARD1 heterodimerization and consequently BRCA1-BARD1 stability, nuclear retention, and localization to DNA damage sites, thus contributing to efficient HR. Our findings define a mechanism for regulation of BRCA1-BARD1 heterodimerization through SIRT2 deacetylation, elucidating a critical upstream signaling event directing BRCA1-BARD1 heterodimerization, which facilitates HR and tumor suppression, and delineating a role for SIRT2 in directing DSB repair by HR.
Topics: Acetylation; BRCA1 Protein; Cell Nucleus; DNA Damage; HEK293 Cells; Homologous Recombination; Humans; Protein Binding; Protein Domains; Protein Multimerization; Protein Stability; Sirtuin 2; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases
PubMed: 33789098
DOI: 10.1016/j.celrep.2021.108921 -
Acta Biochimica Et Biophysica Sinica May 2022Programmed DNA double-strand breaks (DSBs) occur during antigen receptor gene recombination, namely V(D)J recombination in developing B lymphocytes and class switch... (Review)
Review
Programmed DNA double-strand breaks (DSBs) occur during antigen receptor gene recombination, namely V(D)J recombination in developing B lymphocytes and class switch recombination (CSR) in mature B cells. Repair of these DSBs by classical end-joining (c-NHEJ) enables the generation of diverse BCR repertoires for efficient humoral immunity. Deletion of or mutation in c-NHEJ genes in mice and humans confer various degrees of primary immune deficiency and predisposition to lymphoid malignancies that often harbor oncogenic chromosomal translocations. In the absence of c-NHEJ, alternative end-joining (A-EJ) catalyzes robust CSR and to a much lesser extent, V(D)J recombination, but the mechanisms of A-EJ are only poorly defined. In this review, we introduce recent advances in the understanding of A-EJ in the context of V(D)J recombination and CSR with emphases on DSB end processing, DNA polymerases and ligases, and discuss the implications of A-EJ to lymphoid development and chromosomal translocations.
Topics: Animals; DNA; DNA End-Joining Repair; Humans; Immunoglobulin Class Switching; Ligases; Mice; Receptors, Antigen, B-Cell; Translocation, Genetic
PubMed: 35593472
DOI: 10.3724/abbs.2022051