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- Bergink, S, et al.
(author)
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DNA damage triggers nucleotide excision repair-dependent monoubiquitylation of histone H2A
- 2006
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In: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 20:10, s. 1343-1352
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Journal article (peer-reviewed)abstract
- Chromatin changes within the context of DNA repair remain largely obscure. Here we show that DNA damage induces monoubiquitylation of histone H2A in the vicinity of DNA lesions. Ultraviolet (UV)-induced monoubiquitylation of H2A is dependent on functional nucleotide excision repair and occurs after incision of the damaged strand. The ubiquitin ligase Ring2 is required for the DNA damage-induced H2A ubiquitylation. UV-induced ubiquitylation of H2A is dependent on the DNA damage signaling kinase ATR (ATM- and Rad3-related) but not the related kinase ATM (ataxia telangiectasia-mutated). Although the response coincides with phosphorylation of variant histone H2AX, H2AX was not required for H2A ubiquitylation. Together our data show that monoubiquitylation of H2A forms part of the cellular response to UV damage and suggest a role of this modification in DNA repair-induced chromatin remodeling.
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| 3. |
- Bott, LC, et al.
(author)
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The polyglutamine-expanded androgen receptor responsible for spinal and bulbar muscular atrophy inhibits the APC/C(Cdh1) ubiquitin ligase complex
- 2016
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 27703-
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Journal article (peer-reviewed)abstract
- Polyglutamine expansion in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA), an X-linked neuromuscular disease that is fully manifest only in males. It has been suggested that proteins with expanded polyglutamine tracts impair ubiquitin-dependent proteolysis due to their propensity to aggregate, but recent studies indicate that the overall activity of the ubiquitin-proteasome system is preserved in SBMA models. Here we report that AR selectively interferes with the function of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), which, together with its substrate adaptor Cdh1, is critical for cell cycle arrest and neuronal architecture. We show that both wild-type and mutant AR physically interact with the APC/CCdh1 complex in a ligand-dependent fashion without being targeted for proteasomal degradation. Inhibition of APC/CCdh1 by mutant but not wild-type AR in PC12 cells results in enhanced neurite outgrowth which is typically followed by rapid neurite retraction and mitotic entry. Our data indicate a role of AR in neuronal differentiation through regulation of APC/CCdh1 and suggest abnormal cell cycle reactivation as a pathogenic mechanism in SBMA.
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| 4. |
- Dantuma, NP, et al.
(author)
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A dynamic ubiquitin equilibrium couples proteasomal activity to chromatin remodeling
- 2006
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In: The Journal of cell biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 173:1, s. 19-26
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Journal article (peer-reviewed)abstract
- Protein degradation, chromatin remodeling, and membrane trafficking are critically regulated by ubiquitylation. The presence of several coexisting ubiquitin-dependent processes, each of crucial importance to the cell, is remarkable. This brings up questions on how the usage of this versatile regulator is negotiated between the different cellular processes. During proteotoxic stress, the accumulation of ubiquitylated substrates coincides with the depletion of ubiquitylated histone H2A and chromatin remodeling. We show that this redistribution of ubiquitin during proteotoxic stress is a direct consequence of competition for the limited pool of free ubiquitin. Thus, the ubiquitin cycle couples various ubiquitin-dependent processes because of a rate-limiting pool of free ubiquitin. We propose that this ubiquitin equilibrium may allow cells to sense proteotoxic stress in a genome-wide fashion.
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| 5. |
- Dantuma, NP, et al.
(author)
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Ubiquitin versus misfolding: The minimal requirements for inclusion body formation
- 2016
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In: The Journal of cell biology. - : Rockefeller University Press. - 1540-8140 .- 0021-9525. ; 213:2, s. 147-149
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Journal article (peer-reviewed)abstract
- Ubiquitin-containing inclusion bodies are characteristic features of numerous neurodegenerative diseases, but whether ubiquitin plays a functional role in the formation of these protein deposits is unclear. In this issue, Bersuker et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201511024) report that protein misfolding without ubiquitylation is sufficient for translocation into inclusion bodies.
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| 6. |
- Giovannucci, TA, et al.
(author)
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Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound
- 2021
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In: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 12:10, s. 914-
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Journal article (peer-reviewed)abstract
- Malignant cells display an increased sensitivity towards drugs that reduce the function of the ubiquitin-proteasome system (UPS), which is the primary proteolytic system for destruction of aberrant proteins. Here, we report on the discovery of the bioactivatable compound CBK77, which causes an irreversible collapse of the UPS, accompanied by a general accumulation of ubiquitylated proteins and caspase-dependent cell death. CBK77 caused accumulation of ubiquitin-dependent, but not ubiquitin-independent, reporter substrates of the UPS, suggesting a selective effect on ubiquitin-dependent proteolysis. In a genome-wide CRISPR interference screen, we identified the redox enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) as a critical mediator of CBK77 activity, and further demonstrated its role as the compound bioactivator. Through affinity-based proteomics, we found that CBK77 covalently interacts with ubiquitin. In vitro experiments showed that CBK77-treated ubiquitin conjugates were less susceptible to disassembly by deubiquitylating enzymes. In vivo efficacy of CBK77 was validated by reduced growth of NQO1-proficient human adenocarcinoma cells in nude mice treated with CBK77. This first-in-class NQO1-activatable UPS inhibitor suggests that it may be possible to exploit the intracellular environment in malignant cells for leveraging the impact of compounds that impair the UPS.
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| 7. |
- Hafrén, Jonas, et al.
(author)
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Fiber- and fine fractions-derived effects on pulp quality as a result of mechanical pulp refining consistency
- 2014
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In: Wood Science and Technology. - : Springer Science and Business Media LLC. - 0043-7719 .- 1432-5225. ; 48, s. 737-753
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Journal article (peer-reviewed)abstract
- High-yield pulping of wood chips using low-consistency (LC) refining in combination with primary-stage high-consistency (HC) refining has previously been shown to produce paper with quality parameters (tensile strength and light-scattering coefficient) commonly targeted for newsprint with significantly less refining energy input than using only HC refining. However, questions remain on the differences in the refining action between the two refiner types and for high-yield pulping, the refiner energy demand is a crucial process parameter. Therefore, fines- and fiber-fraction development in HC and LC refining has been studied in detail using Bauer-McNett fractionation, and the respective tensile strengths of the different fractions have been compared. Quantitative and qualitative (morphological) characteristics of the isolated fine fractions have also been analyzed in detail using a newly developed automated fluorescence microscopy method and scanning electron microscopy. The results suggest the difference in LC/HC pulp properties (strength and optical) is partly derived from deviating fiber and fines morphologies and mass balances. The quality of the fines generated during HC and LC refining also differs. LC-refined pulps contain thinner fibrillar fines (thread-like) and HC-refined pulps broader fibrils such as lamellae-type fines. Flake-like fines from the outer fiber wall decreased in relative amount with energy input.
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| 10. |
- Richard, TJC, et al.
(author)
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K63-linked ubiquitylation induces global sequestration of mitochondria
- 2020
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 22334-
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Journal article (peer-reviewed)abstract
- Even though K63-linked polyubiquitin chains do not target proteins for proteasomal degradation, they play nevertheless a complementary protective role in maintaining protein homeostasis by directing malfunctioning proteins and organelles to inclusion bodies or autophagosomes. A paradigm for this process is the sequestration and autophagic degradation of dysfunctional mitochondria. Although studies have shown that K63-ubiquitylation of mitochondrial proteins by the ubiquitin ligase Parkin is important in this process, it is presently not clear if this modification also suffices to initiate this cascade of events. To address this question, we have engineered the ubiquitin ligase ProxE3, which in an inducible manner synthesizes K63-linked ubiquitin chains on the surface of mitochondria. We found that the presence of K63-linked ubiquitin chains on mitochondria resulted in the recruitment of the ubiquitin adaptor p62 and induced a dramatic redistribution of mitochondria, which was reminiscent to the Parkin-facilitated sequestration in response to mitochondrial uncoupler. However, ProxE3 did not induce autophagic degradation of mitochondria. Our data show that K63-linked ubiquitin chains at the mitochondrial membrane are sufficient for the induction of mitochondrial sequestration, but not mitophagy, without the need of extrinsically inflicting mitochondrial dysfunction.
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