| 1. |
|
|
| 2. |
|
|
| 3. |
- Bergink, S, et al.
(author)
-
DNA damage triggers nucleotide excision repair-dependent monoubiquitylation of histone H2A
- 2006
-
In: Genes & development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 20:10, s. 1343-1352
-
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.
|
|
| 4. |
- Bergink, S, et al.
(author)
-
Recognition of DNA damage by XPC coincides with disruption of the XPC-RAD23 complex
- 2012
-
In: The Journal of cell biology. - : Rockefeller University Press. - 1540-8140 .- 0021-9525. ; 196:6, s. 681-688
-
Journal article (peer-reviewed)abstract
- The recognition of helix-distorting deoxyribonucleic acid (DNA) lesions by the global genome nucleotide excision repair subpathway is performed by the XPC–RAD23–CEN2 complex. Although it has been established that Rad23 homologs are essential to protect XPC from proteasomal degradation, it is unclear whether RAD23 proteins have a direct role in the recognition of DNA damage. In this paper, we show that the association of XPC with ultraviolet-induced lesions was impaired in the absence of RAD23 proteins. Furthermore, we show that RAD23 proteins rapidly dissociated from XPC upon binding to damaged DNA. Our data suggest that RAD23 proteins facilitate lesion recognition by XPC but do not participate in the downstream DNA repair process.
|
|
| 5. |
- Biverstal, H, et al.
(author)
-
Functionalization of amyloid fibrils via the Bri2 BRICHOS domain
- 2020
-
In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 21765-
-
Journal article (peer-reviewed)abstract
- Amyloid fibrils are mechanically robust and partly resistant to proteolytic degradation, making them potential candidates for scaffold materials in cell culture, tissue engineering, drug delivery and other applications. Such applications of amyloids would benefit from the possibility to functionalize the fibrils, for example by adding growth factors or cell attachment sites. The BRICHOS domain is found in a family of human proteins that harbor particularly amyloid-prone regions and can reduce aggregation as well as toxicity of several different amyloidogenic peptides. Recombinant human (rh) BRICHOS domains have been shown to bind to the surface of amyloid-β (Aβ) fibrils by immune electron microscopy. Here we produce fusion proteins between mCherry and rh Bri2 BRICHOS and show that they can bind to different amyloid fibrils with retained fluorescence of mCherry in vitro as well as in cultured cells. This suggests a “generic” ability of the BRICHOS domain to bind fibrillar surfaces that can be used to synthesize amyloid decorated with different protein functionalities.
|
|
| 6. |
- Bot, C, et al.
(author)
-
Independent mechanisms recruit the cohesin loader protein NIPBL to sites of DNA damage
- 2017
-
In: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 130:6, s. 1134-1146
-
Journal article (peer-reviewed)abstract
- NIPBL is required to load the cohesin complex on to DNA. While the canonical role of cohesin is to couple replicated sister chromatids together until the onset of mitosis, it also promotes tolerance to DNA damage. Here we show that NIPBL is recruited to DNA damage throughout the cell cycle via independent mechanisms, influenced by type of damage. Firstly, the heterochromatin protein HP1γ recruits NIPBL to DSBs through the corresponding HP1-binding motif within the N-terminus. In contrast, the C-terminal HEAT repeat domain is unable to recruit NIPBL to DSBs but independently targets NIPBL to laser microirradiation induced DNA damage. Each mechanism is dependent on the RNF8/RNF168 ubiquitylation pathway, while the recruitment of the HEAT repeat domain requires further ATM/ATR activity. Thus, NIPBL has evolved a sophisticated response to damaged DNA that is influenced by the form of damage, suggesting a highly dynamic role for NIPBL in maintaining genomic stability.
|
|
| 7. |
|
|
| 8. |
- Bott, LC, et al.
(author)
-
The polyglutamine-expanded androgen receptor responsible for spinal and bulbar muscular atrophy inhibits the APC/C(Cdh1) ubiquitin ligase complex
- 2016
-
In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 27703-
-
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.
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
- Dantuma, NP, et al.
(author)
-
A dynamic ubiquitin equilibrium couples proteasomal activity to chromatin remodeling
- 2006
-
In: The Journal of cell biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 173:1, s. 19-26
-
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.
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
|
|
| 19. |
|
|
| 20. |
- Dantuma, NP, et al.
(author)
-
Stressing the ubiquitin-proteasome system
- 2010
-
In: Cardiovascular research. - : Oxford University Press (OUP). - 1755-3245 .- 0008-6363. ; 85:2, s. 263-271
-
Journal article (peer-reviewed)
|
|
| 21. |
- Dantuma, NP, et al.
(author)
-
The price of longevity
- 2020
-
In: Aging. - : Impact Journals, LLC. - 1945-4589. ; 12:22, s. 22350-22351
-
Journal article (other academic/artistic)
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
- Dantuma, NP, et al.
(author)
-
Ubiquitin versus misfolding: The minimal requirements for inclusion body formation
- 2016
-
In: The Journal of cell biology. - : Rockefeller University Press. - 1540-8140 .- 0021-9525. ; 213:2, s. 147-149
-
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.
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
|
|
| 30. |
- Giovannucci, TA, et al.
(author)
-
Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound
- 2021
-
In: Cell death & disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 12:10, s. 914-
-
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.
|
|
| 31. |
|
|
| 32. |
- Godderz, D, et al.
(author)
-
The deubiquitylating enzyme Ubp12 regulates Rad23-dependent proteasomal degradation
- 2017
-
In: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 130:19, s. 3336-
-
Journal article (peer-reviewed)abstract
- The consecutive actions of the ubiquitin-selective segregase Cdc48 and the ubiquitin shuttle factor Rad23 result in the delivery of ubiquitylated proteins at the proteasome. Here, we show that the deubiquitylating enzyme Ubp12 interacts with Cdc48 and regulates proteasomal degradation of Rad23-dependent substrates. Overexpression of Ubp12 results in stabilization of Rad23-dependent substrates. We show that Ubp12 removes short ubiquitin chains from the N-terminal ubiquitin-like domain (UbL) of Rad23. Preventing ubiquitylation of Rad23 by substitution of lysine residues within the UbL domain, Rad23UbLK0, does not affect the non-proteolytic role of Rad23 in DNA repair but causes an increase in ubiquitylated cargo bound to the UBA2 domains of Rad23 and recapitulates the stabilization of Rad23-dependent substrates observed upon overexpression of Ubp12. Expression of Rad23UbLK0 or overexpression of Ubp12 impairs the ability of yeast to cope with proteotoxic stress consistent with inefficient clearance of misfolded proteins by the ubiquitin/proteasome system. Our data suggest that ubiquitylation of Rad23 plays a stimulatory role in the degradation of ubiquitylated substrates by the proteasome.
|
|
| 33. |
- Heessen, S, et al.
(author)
-
Functional p53 chimeras containing the Epstein-Barr virus Gly-Ala repeat are protected from Mdm2- and HPV-E6-induced proteolysis
- 2002
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 99:3, s. 1532-1537
-
Journal article (peer-reviewed)abstract
- Functional inactivation of the tumor suppressor protein p53 by accelerated ubiquitin/proteasome-dependent proteolysis is a common event in tumor progression. Proteasomal degradation is inhibited by the Gly-Ala repeat (GAr) of the Epstein–Barr virus nuclear antigen-1, which acts as a transferable element on a variety of proteasomal substrates. We demonstrate that p53 chimeras containing GAr domains of different lengths and positions within the protein are protected from proteolysis induced by the ubiquitin ligases murine double minute 2 and E6-associated protein but are still ubiquitinated and retain the capacity to interact with the S5a ubiquitin-binding subunit of the proteasome. The GAr chimeras transactivate p53 target genes, induce cell cycle arrest and apoptosis, and exhibit improved growth inhibitory activity in tumor cells with impaired endogenous p53 activity.
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
|
|
| 37. |
|
|
| 38. |
|
|
| 39. |
|
|
| 40. |
|
|
| 41. |
|
|
| 42. |
|
|
| 43. |
|
|
| 44. |
|
|
| 45. |
|
|
| 46. |
- Lindsten, K, et al.
(author)
-
GFP reporter mouse models of UPS proteolytic function
- 2006
-
In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 20:7, s. 1027-author
-
Journal article (other academic/artistic)
|
|
| 47. |
- Lindsten, K, et al.
(author)
-
GFP reporter mouse models of UPS proteolytic function
- 2006
-
In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 20:7, s. 1027-1027
-
Journal article (other academic/artistic)
|
|
| 48. |
|
|
| 49. |
- Lindsten, K, et al.
(author)
-
Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation
- 2002
-
In: The Journal of cell biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 157:3, s. 417-427
-
Journal article (peer-reviewed)abstract
- Loss of neurons in neurodegenerative diseases is usually preceded by the accumulation of protein deposits that contain components of the ubiquitin/proteasome system. Affected neurons in Alzheimer's disease often accumulate UBB+1, a mutant ubiquitin carrying a 19–amino acid C-terminal extension generated by a transcriptional dinucleotide deletion. Here we show that UBB+1 is a potent inhibitor of ubiquitin-dependent proteolysis in neuronal cells, and that this inhibitory activity correlates with induction of cell cycle arrest. Surprisingly, UBB+1 is recognized as a ubiquitin fusion degradation (UFD) proteasome substrate and ubiquitinated at Lys29 and Lys48. Full blockade of proteolysis requires both ubiquitination sites. Moreover, the inhibitory effect was enhanced by the introduction of multiple UFD signals. Our findings suggest that the inhibitory activity of UBB+1 may be an important determinant of neurotoxicity and contribute to an environment that favors the accumulation of misfolded proteins.
|
|
| 50. |
|
|
