A chemical-genetic screen to unravel the genetic network of
            <i>CDC28/CDK1</i>
            links ubiquitin and Rad6–Bre1 to cell cycle progression

Zimmermann, Christine; Chymkowitch, Pierre; Eldholm, Vegard; Putnam, Christopher D.; Lindvall, Jessica M.; Omerzu, Manja; Bjørås, Magnar; Kolodner, Richard D.; Enserink, Jorrit M.

doi:10.1073/pnas.1115885108

Cited by 32 publications

(56 citation statements)

References 38 publications

(43 reference statements)

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“…2E). Intriguingly, most of these biological functions have been reported by others (9,12,15,(19)(20)(21)(22), further validating the data from our mass spectrometry analysis and the related assays. However, when cells were irradiated with X rays, there was an obvious functional shift of the interaction networks of the RAD6A interaction partners.…”

Section: Resultssupporting

confidence: 67%

Interactome Analysis Reveals a Novel Role for RAD6 in the Regulation of Proteasome Activity and Localization in Response to DNA Damage

Wang

et al. 2017

Molecular and Cellular Biology

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RAD6, an E2 ubiquitin-conjugating enzyme, is a key node for determining different DNA damage repair pathways, controlling both the error-prone and the error-free DNA damage repair pathways through differential regulation of the ubiquitination of the proliferating cell nuclear antigen (PCNA) protein. However, whether other pathways are involved in the RAD6-mediated regulation of DNA damage repair is still unclear. To deeply understand the molecular mechanisms of RAD6 in DNA damage repair, we performed a proteomic analysis and identified the changes of the protein-protein interaction (PPI) networks of RAD6 before and after X-ray irradiation. Furthermore, our study indicated that a proteasome-related event is likely involved in the DNA damage repair process. Moreover, we found that RAD6 promotes proteasome activity and nuclear translocation by enhancing the degradation of PSMF1 and the lamin B receptor (LBR). Therefore, we provide a novel pathway that is employed by RAD6 in response to DNA damage.

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Section: Resultssupporting

confidence: 67%

Interactome Analysis Reveals a Novel Role for RAD6 in the Regulation of Proteasome Activity and Localization in Response to DNA Damage

Wang

et al. 2017

Molecular and Cellular Biology

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“…These discoveries are supported by report in the biomedical literature (Hartman et al, 2009;Zimmermann et al, 2011).…”

Section: Discussionsupporting

confidence: 62%

Inferring Transcriptional Regulatory Relationships Among Genes in Breast Cancer: An Application of Bayes' Theorem

Adabor¹,

Acquaah‐Mensah²,

Oduro³

2014

IJSP

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The introduction of Deoxyribonucleic acid (DNA) microarray technologies provides a means of measuring the expression of thousands of genes simultaneously. It has generally sought to revolutionalize biological research by significantly elucidating biological processes. Gene networks may be inferred from such microarray data. Bayes' theorem, in this work is applied to the problem of inferring new transcriptional regulatory relationships among gene products in Breast Cancer. A compendium of human breast epithelial cell probe level microarray data from the Gene Expression Omnibus (GEO) repository was subjected to the Robust Multiarray Average (RMA) procedure for normalization and background correction. A subset of the resulting expression matrix consisting of the expression values of only relevant probe-set identifiers (IDs) representing the genes of interest in the data were extracted with a LISP code. This subset was supplied to a Bayesian Network inference learning algorithm to unearth new regulatory relationships from the data. Variations in parameters of the learning algorithms resulted in the prediction of at least 10 new relationships among genes in breast cancer. Among these were the direct regulatory signaling relationship between S-phase kinase associated protein 2 (SKP2) and the Cell division cycle 25A (CDC25A) and that between the cyclin-dependent kinases regulatory subunit 1 (CKS1B / CDC28) and E2F transcription factor 3 (E2F3). The identified causal networks are potentially useful for understanding complex drug actions and dysfunctional signaling in breast cancer.

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“…Since the cdc28-as mutant is reduced by sixfold in overall in vitro activity in the absence of inhibitor (Bishop et al 2000), we surmise that the loss of Abp1p phosphorylation in the doublemutant strain is the result of simultaneous partial reduction in the activity of both kinases. We show here that the pho85-as mutant is definitely inhibited further by addition of 1NM-PP1 (Supporting Information, Figure S1), and the specific inhibition of the cdc28-as mutant by this compound has been previously demonstrated (Bishop et al 2000;Zimmermann et al 2011).…”

Section: Cdc28p and Pho85p Phosphorylate Abp1pmentioning

confidence: 86%

The Importance of Conserved Features of Yeast Actin-Binding Protein 1 (Abp1p): The Conditional Nature of Essentiality

Garcı́a¹,

Stollar

Davidson

2012

Genetics

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Saccharomyces cerevisiae Actin-Binding Protein 1 (Abp1p) is a member of the Abp1 family of proteins, which are in diverse organisms including fungi, nematodes, flies, and mammals. All proteins in this family possess an N-terminal Actin Depolymerizing Factor Homology (ADF-H) domain, a central Proline-Rich Region (PRR), and a C-terminal SH3 domain. In this study, we employed sequence analysis to identify additional conserved features of the family, including sequences rich in proline, glutamic acid, serine, and threonine amino acids (PEST), which are found in all family members examined, and two motifs, Conserved Fungal Motifs 1 and 2 (CFM1 and CFM2), that are conserved in fungi. We also discovered that, similar to its mammalian homologs, Abp1p is phosphorylated in its PRR. This phosphorylation is mediated by the Cdc28p and Pho85p kinases, and it protects Abp1p from proteolysis mediated by the conserved PEST sequences. We provide evidence for an intramolecular interaction between the PRR region and SH3 domain that may be affected by phosphorylation. Although deletion of CFM1 alone caused no detectable phenotype in any genetic backgrounds or conditions tested, deletion of this motif resulted in a significant reduction of growth when it was combined with a deletion of the ADF-H domain. Importantly, this result demonstrates that deletion of highly conserved domains on its own may produce no phenotype unless the domains are assayed in conjunction with deletions of other functionally important elements within the same protein. Detection of this type of intragenic synthetic lethality provides an important approach for understanding the function of individual protein domains or motifs.

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A chemical-genetic screen to unravel the genetic network of CDC28/CDK1 links ubiquitin and Rad6–Bre1 to cell cycle progression

Cited by 32 publications

References 38 publications

Interactome Analysis Reveals a Novel Role for RAD6 in the Regulation of Proteasome Activity and Localization in Response to DNA Damage

Interactome Analysis Reveals a Novel Role for RAD6 in the Regulation of Proteasome Activity and Localization in Response to DNA Damage

Inferring Transcriptional Regulatory Relationships Among Genes in Breast Cancer: An Application of Bayes' Theorem

The Importance of Conserved Features of Yeast Actin-Binding Protein 1 (Abp1p): The Conditional Nature of Essentiality

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