Distinct regulation of Ubc13 functions by the two ubiquitin-conjugating enzyme variants Mms2 and Uev1A

Andersen, Parker L.; Zhou, Honglin; Pastushok, Landon; Moraes, Trevor F.; McKenna, Sean Andrew; Ziola, Barry; Ellison, M.; Dixit, Vishva M.; Xiao, Wei

doi:10.1083/jcb.200502113

Cited by 155 publications

(211 citation statements)

References 57 publications

(100 reference statements)

Supporting

Mentioning

198

Contrasting

Unclassified

Order By: Relevance

“…Ubc13 is the E2 that was shown, as part of a complex with another partner, Uev1a, to be involved in many cases of assembly of such chains. 35,36 However, several cases were described recently in which 'canonical' E2s were also shown to be involved in generation of such chains. 37,38 While a Ubc13 homolog was described also in the fly, 39 it appears from our in vitro data that a 'canonical' E2 such as UbcD1 can also be involved in the process.…”

Section: Resultsmentioning

confidence: 99%

Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways

et al. 2007

View full text Add to dashboard Cite

Inhibitors of apoptosis proteins (IAPs) suppress cell death by inactivating proapoptotic regulators, and therefore play important roles in controlling apoptosis in normal and malignant cells. Many IAPs are ubiquitin ligases, and their activity is mediated via ubiquitination and subsequent degradation of their targets. Here we corroborate a previous observation that DIAP1 (Drosophila IAP1) can be degraded via a two-step mechanism: (i) limited caspase-mediated cleavage and (ii) degradation of the released fragment via the ubiquitin N-end rule pathway. Yet, we demonstrate that this pathway is not the only one involved in DIAP1 degradation, and the intact protein can be degraded independent of prior caspase cleavage. Importantly, this mode of degradation does not require the RING-finger-mediated autoubiquitinating activity of DIAP1, believed to target many RING-finger E3s for self-destruction. Our preliminary data suggest that DIAP2 mediates DIAP1 degradation, suggesting a novel regulatory loop within the apoptotic pathway. Studying the role of the autoubiquitinating activity of DIAP1, we demonstrate that it does not involve formation of Lys48-based polyubiquitin chains, but probably chains linked via Lys63. Our preliminary data suggest that the autoubiquitination serves to attenuate the ligase activity of DIAP1 towards its exogenous substrates. Recent studies indicate that ubiquitination plays an important role in regulating apoptosis. This is partially mediated by the inhibitors of apoptosis proteins (IAPs), a centrally important group of cell death regulators, many of them are ubiquitin ligases. IAPs suppress cell death by inactivating different proapoptotic factors, some by targeting them for ubiquitination and subsequent proteasomal degradation. At least eight IAPs have been identified in mammals. In Drosophila melanogaster, expression of DIAP1 and DIAP2 1 can suppress apoptosis that occurs both during normal development as well as following overexpression of proapoptotic factors such as Reaper (Rpr). 2 Loss of DIAP1 function results in early embryonic death as a consequence of massive apoptosis. [3][4][5] The IAP family is characterized structurally by one-three Nterminal copies of Baculovirus IAP Repeat (BIR) domains. DIAP1 contains two copies of BIR that bind effector and initiator caspases. In some cases, this binding leads to ubiquitination and subsequent degradation of the caspase. 2 IAP-mediated inactivation of caspases is effectively inhibited by a family of proapoptotic proteins that share an IAP-binding tetra-peptide motif at their N-termini. Among those proteins are Smac/Diablo in mammals, and Rpr, Hid and Grim (RHG) in Drosophila. It was shown that RHG proteins abrogate effectively DIAP1-mediated inactivation of Dronc and DrICE. 6 DIAP1 contains also a C-terminal RING-finger motif that serves to recruit the E2 component of the ubiquitin conjugation machinery. For RING-finger E3s, their best-characterized activity is self-ubiquitination thought to regulate their cellular level, but it is assumed th...

show abstract

Section: Resultsmentioning

confidence: 99%

Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways

et al. 2007

View full text Add to dashboard Cite

show abstract

“…As UbcH7 is also known to mediate K63-linked poly-ubiquitination of TRAF6 [45], there might be redundancy for TRAF6 autoubiquitination, but not for IKKg poly-ubiquitination by TRAF6. Furthermore, RNA interference-mediated knock-down of either Ubc13 or Uev1A abolishes TRAF6-induced NF-kB activation, IKKg poly-ubiquitination and p65 nuclear translocation upon LPS stimulation [46]. Finally, TAB2, TAB3 and IKKg also become K63-poly-ubiquitinated by TRAF6 [22, 47 -49].…”

Section: Il-1r and Tlr-4 Signaling To Nf-kbmentioning

confidence: 99%

“…Ubc13 also plays an essential role in TNF-induced NFkB activation, as macrophages and splenocytes isolated from Ubc13 +/-mice stimulated with TNF show impaired IkBa degradation [43]. Furthermore, siRNA directed against either Ubc13 or Uev1A abolishes TRAF2-mediated signaling to NF-kB [46]. In contrast, Yamamoto et al demonstrated that Ubc13-deficient murine embryonic fibroblasts show normal activation of NF-kB and JNK in response to TNF [44].…”

Section: Verstrepen Et Almentioning

confidence: 99%

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

Verstrepen

Bekaert

Chau

et al. 2008

Cell. Mol. Life Sci.

384

279

View full text Add to dashboard Cite

Abstract. Toll-like receptors (TLRs) as well as the receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kB (NF-kB). TLR, IL-1R and TNF-R signaling to NF-kB converge on a common IkB kinase complex that phosphorylates the NF-kB inhibitory protein IkBa. However, upstream signaling components are in large part receptor-specific. Nevertheless, the principles of signaling are similar, involving the recruitment of specific adaptor proteins and the activation of kinase cascades in which protein-protein interactions are controlled by poly-ubiquitination. In this review, we will discuss our current knowledge of NF-kB signaling in response to TLR-4, TNF-R and IL-1R stimulation, with a special focus on the similarities and dissimilarities among these pathways.Keywords. Toll-like receptor 4, interleukin-1, tumor necrosis factor, NF-kB, signal transduction. NF-kB, does it still need to be introduced?Nuclear factor kB (NF-kB) is the generic name of a family of transcription factors that regulate the expression of a large number of genes involved in immune and inflammatory responses, as well as in cell survival, cell proliferation and cell differentiation. NFkB transcription factors are activated in response to various stimuli, including cytokines, infectious agents, injury and other stressful conditions requiring rapid reprogramming of gene expression. Inappropriate activation of the NF-kB signaling pathway is implicated in the pathogenesis of chronic inflammation and autoimmunity, certain hereditary disorders and various cancers. In mammals, the NF-kB family consists of five proteins sharing a highly conserved Rel homology domain: c-Rel, RelB, p65 (= RelA), p105 (= NF-kB1) and p100 (=NF-kB2). The first three contain Cterminal transactivation domains, while the others share a long C-terminal domain with multiple copies of ankyrin repeats, which inhibit their activation.

show abstract

“…Sequence and functional homologs of all proteins involved in error-free DDT, including Mms2 [140], Ubc13 [141] and Rad5 [142,143], have been found in mammals, plants and other higher eukaryotes [144,145]. For a few limited examples, suppression of the above genes resulted in phenotypes reminiscent of the corresponding yeast mutants [143,146,147].…”

Section: Error-free Ddtmentioning

confidence: 99%

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Andersen¹,

Xiao³

2007

Cell Res

Self Cite

183

186

View full text Add to dashboard Cite

npg In addition to well-defined DNA repair pathways, all living organisms have evolved mechanisms to avoid cell death caused by replication fork collapse at a site where replication is blocked due to disruptive covalent modifications of DNA. The term DNA damage tolerance (DDT) has been employed loosely to include a collection of mechanisms by which cells survive replication-blocking lesions with or without associated genomic instability. Recent genetic analyses indicate that DDT in eukaryotes, from yeast to human, consists of two parallel pathways with one being error-free and another highly mutagenic. Interestingly, in budding yeast, these two pathways are mediated by sequential modifications of the proliferating cell nuclear antigen (PCNA) by two ubiquitination complexes Rad6-Rad18 and Mms2-Ubc13-Rad5. Damage-induced monoubiquitination of PCNA by Rad6-Rad18 promotes translesion synthesis (TLS) with increased mutagenesis, while subsequent polyubiquitination of PCNA at the same K164 residue by Mms2-Ubc13-Rad5 promotes error-free lesion bypass. Data obtained from recent studies suggest that the above mechanisms are conserved in higher eukaryotes. In particular, mammals contain multiple specialized TLS polymerases. Defects in one of the TLS polymerases have been linked to genomic instability and cancer. DNA damage toleranceIn the presence of spontaneous or carcinogen-induced DNA damage, living cells have to maintain and complete DNA synthesis or risk replication fork collapse. Since the process of DNA licensing is to ensure the genome is duplicated once and only once during each cell cycle, stalled or collapsed replication forks may not be able to restart, which often results in double-strand breaks (DSBs) and causes compromised genome integrity or cell death. In addition to highly conserved DNA repair pathways, all living organisms have evolved schemes to ensure continuation of DNA synthesis in the presence of damage. These schemes were originally termed DNA postreplication repair (PRR) due to observations of transient shortened nascent DNA structures following S phase in response to DNA damage. In bacteria and unicellular yeast, these shortened DNA segments can be measured by an alkaline sedimentation assay [1] or directly observed in electron micrographs [2]. In wild-type cells, these truncated DNA segments were restored to full length following a short recovery time. One typical experiment [1] involved the restoration of the nascent strand following UV exposure in nucleotide excision repair (NER)-deficient cells and was originally assumed to represent a mechanism of DNA repair. However, further investigation revealed that, although the nascent fragments were re-annealed, the original UV-induced pyrimidine dimers, which were responsible for the generation of single-strand gaps, often persisted in the genome [3,4]. It was argued that the replication-blocking lesion was not necessarily corrected, but rather transiently bypassed and carried over to the next generation. Perhaps it is more beneficial for the organi...

show abstract

Distinct regulation of Ubc13 functions by the two ubiquitin-conjugating enzyme variants Mms2 and Uev1A

Cited by 155 publications

References 57 publications

Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways

Regulation of the Drosophila ubiquitin ligase DIAP1 is mediated via several distinct ubiquitin system pathways

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA

Contact Info

Product

Resources

About