Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has recently been shown that the UMP1 gene of Saccharomyces cerevisiae encodes a small. short-lived protein engaged in 20S proteasome formation. The results presented in this paper demonstrate that ULMP1 expression is induced by the DNA damaging agents methyl methanesulfonate (MMS) and UV light as well as by hydroxyurea (HU), an inhibitor of DNA replication. MMS induction of UMP1 expression occurs at the transcriptional level and is independent of the activity of the regulatory checkpoint kinases encoded by MEC1. RAD53 or DUN1. It is also shown that the disruption of UMP1 causes increased sensitivity of yeast cells to killing by UV radiation, but only slight sensitivity to HU treatment, and does not cause any increase in the killing effect of MMS.
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PMID:Expression of UMP1 is inducible by DNA damage and required for resistance of S. cerevisiae cells to UV light. 1097 53

Treatment of cells with genotoxic agents affects protein degradation in both positive and negative ways. Exposure of S. cerevisiae to the alkylating agent MMS resulted in activation of genes that are involved in ubiquitin- and 26S proteasome-dependent protein degradation. This process partially overlaps with the activation of the ER-associated protein degradation pathway. The DNA repair protein Rad23p and its mammalian homologues have been shown to inhibit degradation of specific substrates in response to DNA damage. Particularly the recently identified inhibition of degradation by mouse Rad23 protein (mHR23) of the associated nucleotide excision repair protein XPC was shown to stimulate DNA repair.Recently, it was shown that Rad23p and the mouse homologue mHR23B also associate with Png1p, a deglycosylation enzyme. Png1p-mediated deglycosylation plays a role in ER-associated protein degradation after accumulation of malfolded proteins in the endoplasmic reticulum. Thus, if stabilization of proteins that are associated with the C-terminus of Rad23p is a general phenomenon, then Rad23 might be implicated in the stimulation of ER-associated protein degradation as well. Interestingly, the recently identified HHR23-like protein Mif1 is also thought to play a role in ER-associated protein degradation. The MIF1 gene is strongly activated in response to ER-stress. Mif1 contains a ubiquitin-like domain which is most probably involved in binding to S5a, a subunit of the 19S regulatory complex of the 26S proteasome. On the basis of its localization in the ER-membrane, it is hypothesized that Mif1 could play a role in the translocation of the 26S proteasome towards the ER-membrane, thereby enhancing ER-associated protein degradation.
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PMID:A role for Rad23 proteins in 26S proteasome-dependent protein degradation? 1180 4

Induction of gene expression in response to DNA damage is important for repairing damaged DNA for cell survival. Previously, we identified a novel zinc finger protein, ZBRK1, which contains a KRAB domain at the N terminus, eight zinc fingers at the center, and a BRCA1-binding region at the C terminus. In a BRCA1-dependent manner, ZBRK1 represses Gadd45a transcription through binding to a specific sequence in intron 3. In addition, ZBRK1-binding sequences are located at the regulatory region of many DNA damage-inducible genes, suggesting that ZBRK1 may have a role in DNA damage response. However, it is unclear how transcription repression by ZBRK1 is relieved subsequent to DNA damage. Here we report that ZBRK1 is rapidly degraded upon treatment with the DNA-damaging agents UV and methyl methanesulfonate. Specific proteasome inhibitors block DNA damage-induced degradation of ZBRK1, and the polyubiquitinated form of ZBRK1 is detectable, suggesting that the ubiquitin-proteasome pathway mediates the degradation of ZBRK1. In both BRCA1-proficient and -deficient cells, ZBRK1 is degraded with similar efficiencies independent of BRCA1 E3 ligase activity. By analysis of a series of ZBRK1 mutants, a 44-amino-acid element located between the N-terminal KRAB domain and the eight zinc fingers was found to be sufficient for the DNA damage-induced degradation of ZBRK1. Cells expressing a ZBRK1 mutant lacking the 44-amino-acid element are hypersensitive to DNA damage and are compromised for Gadd45a derepression. These results indicate that ZBRK1 is a novel target for DNA damage-induced degradation and provide a mechanistic explanation of how ZBRK1 is regulated in response to DNA damage.
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PMID:Degradation of transcription repressor ZBRK1 through the ubiquitin-proteasome pathway relieves repression of Gadd45a upon DNA damage. 1451 99

We report here the existence of interactions between a ubiquitin-conjugating enzyme, Rad6, from rice, Oryza sativa L. cv. Nipponbare (OsRad6), and Sgt1 (OsSgt1), a novel subunit of the SCF ubiquitin ligase complex. Rad6 is not only related to post-replicational repair but also to the proteasome system, while Sgt1 has a function in kinetochore assembly. The relationship between the two is unexpected, but of great interest. The open reading frames of OsRad6 and OsSgt1 encode predicted products of 152 and 367 amino acid residues, respectively, with molecular weights of 17.3 and 40.9kDa. Two-hybrid and pull-down analyses indicated that OsRad6 binds to OsSgt1, and transcripts of both OsRad6 and OsSgt1 were found to be strongly expressed only in the proliferating tissues such as the shoot apical meristem, suggesting that their expression is cell cycle-dependent. The amount of the Rad6 mRNA in cultured cells increased rapidly after division was halted, and mRNA levels of Rad6 and Sgt1 were induced by UV- and DNA-damaging agents such as MMS or H(2)O(2). The Rad6 pathway for repair or the proteasome system may thus require Sgt1 as ubiquitin-conjugating enzyme.
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PMID:Characterization of Rad6 from a higher plant, rice (Oryza sativa L.) and its interaction with Sgt1, a subunit of the SCF ubiquitin ligase complex. 1473 24

Polyubiquitination plays key roles in various proteasome-dependent and independent cellular events. To elucidate roles in stress response of polyubiquitin chains formed via specific chain linkages in mammalian cells, we established NIH3T3 stable cell lines that are capable of conditionally expressing K29R, K48R and K63R ubiquitin mutants, in which the Lys29, Lys48 and Lys63 residues of ubiquitin had been changed to Arg, and we examined the effects of various stresses on their cell viabilities. The expression of K63R ubiquitin mutant decreased viability of the cells post-exposed to ethanol, H(2)O(2) and methyl methanesulfonate (MMS), while that of K48R mutant decreased viability of the cells post-exposed to heat shock as well as ethanol, H(2)O(2) and MMS. Thus, these results suggest that polyubiquitin chains formed via specific chain linkages are involved in the respective stress responses in mammalian cells.
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PMID:Involvement of polyubiquitin chains via specific chain linkages in stress response in mammalian cells. 1632 72

Mammalian DNA polymerase (Pol) delta is essential for DNA replication. It consists of four subunits, p125, p50, p68, and p12. We report the discovery that the p12 subunit is rapidly degraded in cultured human cells by DNA damage or replication stress brought about by treatments with UV, methyl methanesulfonate, hydroxyurea, and aphidicolin. The degradation of p12 is due to an accelerated rate of proteolysis that is inhibited by the proteasome inhibitors, MG132 and lactacystin. UV treatment converts Pol delta in vivo to the three-subunit form lacking p12. This was demonstrated by its isolation using immunoaffinity chromatography. The three-subunit enzyme retains activity on poly(dA)/oligo(dT) templates but is impaired in its ability to extend singly primed M13 templates, clearly indicating that its in vivo functions are likely to be compromised. This transformation of Pol delta by modification of its quaternary structure is reversible in vitro by the addition of the p12 subunit and could represent a novel in vivo mechanism for the modulation of Pol delta function. UV and hydroxyurea-triggered p12 degradation is blocked in ATR(-/-) cells but not in ATM(-/-) cells, thereby demonstrating that p12 degradation is regulated by ATR, the apical kinase that regulates the damage response in S-phase. These findings reveal a novel addition to the cellular repertoire of DNA damage responses that also impacts our understanding of the role of Pol delta in both DNA replication and DNA repair.
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PMID:A novel DNA damage response: rapid degradation of the p12 subunit of dna polymerase delta. 1731 65

Genome wide experiments indicate both proteasome- and vacuole-mediated protein degradation modulate sensitivity to classical DNA-damaging agents. Here, we show that global protein degradation is significantly increased upon methyl methanesulfonate (MMS) exposure. In addition, global protein degradation is similarly increased upon exposure to 4-nitroquinoline-N-oxide (4NQO) and UV and, to a lesser extent, tert-butyl hydroperoxide. The proteasomal inhibitor MG132 decreases both MMS-induced and 4NQO-induced protein degradation, while addition of the vacuolar inhibitor phenylmethanesulfonyl fluoride does not. The addition of both inhibitors grossly inhibits cell growth upon MMS exposure over and above the growth inhibition induced by MMS alone. The MMS-induced protein degradation response remains unchanged in several ubiquitin-proteasome and vacuolar mutants, presumably because these mutants are not totally deficient in either essential pathway. Furthermore, MMS-induced protein degradation is independent of Mec1, Mag1, Rad23, and Rad6, suggesting that the protein degradation response is not transduced through the classical Mec1 DNA damage response pathway or through repair intermediates generated by the base excision, nucleotide excision, or postreplication-DNA repair pathways. These results identify the regulation of protein degradation as an important factor in the recovery of cells from toxicity induced by classical DNA-damaging agents.
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PMID:The protein degradation response of Saccharomyces cerevisiae to classical DNA-damaging agents. 1802 Apr 23

When cells traversing G(1) are irradiated with UV light, two parallel damage checkpoint pathways are activated: Chk1-Cdc25A and p53-p21(WAF1/CIP1), both targeting Cdk2, but the latter inducing a long lasting arrest. In similarly treated S phase-progressing cells, however, only the Cdc25A-dependent checkpoint is active. We have recently found that the p21-dependent checkpoint can be activated and induce a prolonged arrest if S phase cells are damaged with a base-modifying agent, such as methyl methanesulfonate (MMS) and cisplatin. But the mechanistic basis for the differential activation of the p21-dependent checkpoint by different DNA damaging agents is not understood. Here we report that treatment of S phase cells with MMS but not a comparable dose of UV light elicits proteasome-mediated degradation of Cdc6, the assembler of pre-replicative complexes, which allows induced p21 to bind Cdk2, thereby extending inactivation of Cdk2 and S phase arrest. Consistently, enforced expression of Cdc6 largely eliminates the prolonged S phase arrest and Cdk2 inactivation induced with MMS, whereas RNA interference-mediated Cdc6 knockdown not only prolongs such arrest and inactivation but also effectively activates the p21-dependent checkpoint in the UV-irradiated S phase cells.
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PMID:Cdc6 determines utilization of p21(WAF1/CIP1)-dependent damage checkpoint in S phase cells. 1845 79

Ubiquitin-proteasome proteolytic system participates in metabolism of the majority of intracellular proteins and regulation of key cellular processes in eukaryotes. While the structure and functioning of this system is studied rather well, a little is known about regulation of its genes expression. At present time, the only regulatory system of transcription of proteasome genes is found in the yeast Saccharomyces cerevisiae. This system includes Rpn4p-proteasome-associated transcriptional regulator and its binding site called PACE (Proteasome Associated Control Element). To learn more about function of Rpn4p as a transcriptional regulator, there are following questions: 1) is the Rpn4p regulator for PACE-containing genes which encode for components of protein ubiquitinylation system 2) what is the contribution of Rpn4p in stress-activated level of mRNA of proteasome genes. In this work, using semiquantitative RT-PCR we have shown that deletion of RPN4 gene leads to decreasing in mRNA level of the genes of ubiqitination system RAD6, RAD23 and CDC48, while UBI4 mRNA level is increased in this strain. In the presence of alkylating agent methyl methanesulfonate or under heat shock we observed Rpn4 p-dependent elevation of mRNA level of the proteasomal genes RPT4 and RPNS. At the same time, CDC48 mRNA level is decreased in wild type yeast strain upon methyl methanesulfonate treatment. These data indicate that under normal or stress conditions Rpn4p may act as an activator or repressor for the genes of the ubiquitin-proteasome system.
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PMID:[Rpn4p is a positive and negative transcriptional regulator of the ubiquitin-proteasome system]. 1870 11

We have investigated the agonists that activate transfected extracellular signal-regulated kinase 8 (ERK8) in cells, and have found that the most potent activators are hydrogen peroxide, DNA alkylating and cross-linking agents and the poly (ADP-ribose) polymerase inhibitor KU-0058948. The feature shared by all these agents is that they lead to the accumulation of single strand breaks in DNA, suggesting a role for ERK8 in the response to, or repair of, DNA single strand breaks. The DNA alkylating agent MMS also induced the disappearance of endogenous ERK8 by a proteasome-dependent mechanism.
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PMID:Regulation of the activity and expression of ERK8 by DNA damage. 1916 46


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