Defining the Human Deubiquitinating Enzyme Interaction Landscape

Sowa, Mathew E.; Bennett, Eric J.; Gygi, Steven P.; Harper, J. Wade

doi:10.1016/j.cell.2009.04.042

Cited by 1,388 publications

(1,673 citation statements)

References 44 publications

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“…2A). RAD51AP1 interacting with UAF1 was also reported previously, 23,24 however its functional implication remained unknown. Since RAD51AP1 was the only protein implicated in HR repair among the identified, we decided to characterize the physiological significance of the interaction further.…”

Section: The Usp1-uaf1 Complex Interacts With Rad51ap1mentioning

confidence: 92%

The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair

et al. 2016

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USP1 deubiquitinating enzyme and its stoichiometric binding partner UAF1 play an essential role in promoting DNA homologous recombination (HR) repair in response to various types of DNA damaging agents. Deubiquitination of FANCD2 may be attributed to the key role of USP1-UAF1 complex in regulating HR repair, however whether USP1-UAF1 promotes HR repair independently of FANCD2 deubiquitination is not known. Here we show evidence that the USP1-UAF1 complex has a FANCD2-independent function in promoting HR repair. Proteomic search of UAF1-interacting proteins revealed that UAF1 associates with RAD51AP1, a RAD51-interacting protein implicated in HR repair. We show that UAF1 mediates the interaction between USP1 and RAD51AP1, and that depletion of USP1 or UAF1 led to a decreased stability of RAD51AP1. Protein interaction mapping analysis identified some key residues within RAD51AP1 required for interacting with the USP1-UAF1 complex. Cells expressing the UAF1 interactiondeficient mutant of RAD51AP1 show increased chromosomal aberrations in response to Mitomycin C treatment. Moreover, similar to the RAD51AP1 depleted cells, the cells expressing UAF1-interaction deficient RAD51AP1 display persistent RAD51 foci following DNA damage exposure, indicating that these factors regulate a later step during the HR repair. These data altogether suggest that the USP1-UAF1 complex promotes HR repair via multiple mechanisms: through FANCD2 deubiquitination, as well as by interacting with RAD51AP1.

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Section: The Usp1-uaf1 Complex Interacts With Rad51ap1mentioning

confidence: 92%

The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair

et al. 2016

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“…Three systematic studies have mapped the subcellular distributions of human DUBs in cultured cells and the complement of DUBs found in Saccharomyces pombe (128,244,261). FIGURE 4B illustrates prominent subcellular sites of accumulation for individual mammalian DUBs, derived from these studies and from more specific investigations.…”

Section: Dubomicsmentioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

369

384

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Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

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“…Similarly, several DUBs must be incorporated within large macromolecular complexes, such as the 26S proteasome or the COP9 signalosome, to become active (Guterman and Glickman, 2004b;Adler et al, 2008). In a global proteomics approach, using tandem affinitybased pull-outs and bioinformatics for the high confidence identification of interacting proteins of 75 DUBs, Sowa et al (2009) uncovered a large landscape of 774 putatively associated proteins. In this scenario, protein-protein interactions and complex formation add new layers of complexity in the regulation of DUB functions, yet to be explored.…”

Section: Enzymatic Roles and Regulation Of Dubsmentioning

confidence: 99%

“…The actual function of USP33 is still unknown, but some of the disease-causing mutations in VHL block its binding to USP33 suggesting a possible role for this enzyme in VHL protein regulation. Finally, the recent identification of multiple candidate DUB substrates and interacting proteins (Sowa et al, 2009) will likely unveil novel DUB functions in cancer that could help in the identification of additional therapeutic targets.…”

Section: Other Functional Roles For Dubs In Cancermentioning

confidence: 99%

Deubiquitinases in cancer: new functions and therapeutic options

et al. 2011

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Deubiquitinases (DUBs) have fundamental roles in the ubiquitin system through their ability to specifically deconjugate ubiquitin from targeted proteins. The human genome encodes at least 98 DUBs, which can be grouped into 6 families, reflecting the need for specificity in their function. The activity of these enzymes affects the turnover rate, activation, recycling and localization of multiple proteins, which in turn is essential for cell homeostasis, protein stability and a wide range of signaling pathways. Consistent with this, altered DUB function has been related to several diseases, including cancer. Thus, multiple DUBs have been classified as oncogenes or tumor suppressors because of their regulatory functions on the activity of other proteins involved in tumor development. Therefore, recent studies have focused on pharmacological intervention on DUB activity as a rationale to search for novel anticancer drugs. This strategy may benefit from our current knowledge of the physiological regulatory mechanisms of these enzymes and the fact that growth of several tumors depends on the normal activity of certain DUBs. Further understanding of these processes may provide answers to multiple remaining questions on DUB functions and lead to the development of DUB-targeting strategies to expand the repertoire of molecular therapies against cancer.

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Defining the Human Deubiquitinating Enzyme Interaction Landscape

Cited by 1,388 publications

References 44 publications

The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair

The USP1-UAF1 complex interacts with RAD51AP1 to promote homologous recombination repair

Deubiquitylases From Genes to Organism

Deubiquitinases in cancer: new functions and therapeutic options

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