Deubiquitylating Enzymes and DNA Damage Response Pathways

Jacq, Xavier; Kemp, Mark I.; Martin, Niall M.B.; Jackson, Stephen

doi:10.1007/s12013-013-9635-3

Cited by 81 publications

(86 citation statements)

References 208 publications

(254 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…USP3, USP7, USP10, USP11, USP16, USP21, and USP22 are reported to regulate DDR sensor proteins. USP1, USP2, USP4, USP7, USP10, USP11, USP24, USP29, and USP47 are directly implicated in the regulation of DDR repair proteins (20). Single-strand DNA breaks are repaired by nucleotide excision repair (NER) and base excision repair (BER) pathways that deal with various DNA helix-distorting lesions and single-strand breaks; mismatch repair pathways that repair base mismatches and insertions/deletions; the nonhomologous end-joining pathway (NHEJ) and/or homologous recombination (HR) pathways, and the Fanconi anemia (FA) pathway, which in conjunction with certain HR factors act to recognize and repair inter-strand cross-links (ICL) DNA lesions.…”

Section: Usp-associated Mutations and Gene Fusions In Hematologic Malmentioning

confidence: 99%

Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer

2014

View full text Add to dashboard Cite

The ubiquitin-proteasome system (UPS) has emerged as a therapeutic focus and target for the treatment of cancer. The most clinically successful UPS-active agents (bortezomib and lenalidomide) are limited in application to hematologic malignancies, with only marginal efficacy in solid tumors. Inhibition of specific ubiquitin E3 ligases has also emerged as a valid therapeutic strategy, and many targets are currently being investigated. Another emerging and promising approach in regulation of the UPS involves targeting deubiquitinases (DUB). The DUBs comprise a relatively small group of proteins, most with cysteine protease activity that target several key proteins involved in regulation of tumorigenesis, apoptosis, senescence, and autophagy. Through their multiple contacts with ubiquitinated protein substrates involved in these pathways, DUBs provide an untapped means of modulating many important regulatory proteins that support oncogenic transformation and progression. Ubiquitin-specific proteases (USP) are one class of DUBs that have drawn special attention as cancer targets, as many are differentially expressed or activated in tumors or their microenvironment, making them ideal candidates for drug development. This review attempts to summarize the USPs implicated in different cancers, the current status of USP inhibitor-mediated pharmacologic intervention, and future prospects for USP inhibitors to treat diverse cancers. Cancer Res; 74(18); 4955-66. Ó2014 AACR.

show abstract

Section: Usp-associated Mutations and Gene Fusions In Hematologic Malmentioning

confidence: 99%

Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer

2014

View full text Add to dashboard Cite

show abstract

“…Considerable progress has been made in the study of ubiquitin conjugation; however, the study of DUBs is still in its primary stages. Early research has been promising, implicating a number of DUBs, such as USP4 (UNP), USP6 (Tre-2), USP8 (UBPY), and USP28 and UCHL5 (UCH37) in neoplastic disease (17)(18)(19)(20)(21)(22).…”

Section: Diubiquitin Linkagesmentioning

confidence: 99%

“…Subsequent work has confirmed the interaction between USP28 and 53BP1 but found only minor effects on the DNA damage response and no impairment in 53BP1-dependent processes, suggesting that it may not represent an attractive therapeutic target for chemosensitization (18,26). However, its conditional depletion in a mouse model of colorectal cancer led to a significant increase in tumor latency, suggesting that in particular contexts, the modulation of its activity may influence cancer progression (22).…”

Section: Diubiquitin Linkagesmentioning

confidence: 99%

Regulation of USP28 Deubiquitinating Activity by SUMO Conjugation

Zhen

Knobel

Stracker

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: USP28 is a deubiquitinating enzyme implicated in the DNA damage response, Myc stabilization, and cancer progression. Results: USP28 activity is regulated by SUMO conjugation on the N-terminal region. Conclusion:The N-terminal ubiquitin-binding domains of USP28 are not required for polyubiquitin processing. Significance: Cross-talk exists between SUMO and ubiquitin in the regulation of USP28 enzymatic activity.

show abstract

“…The enzymes that remove ubiquitin modifications of DDR proteins have also come under the spotlight as potential targets for small molecule therapeutics in cancer (reviewed in 63,64 ). These deubiquitylating/deubiquitinating enzymes (DUBs) of which ~100 are identifiable in the human genome, hydrolyse the isopeptide bond linking the C-terminal glycine of ubiquitin with a lysine side chain on the target protein or another ubiquitin molecule.…”

Section: Ddr Regulation By Ubiquitin Like Phosphorylation Ubiquitinmentioning

confidence: 99%

“…siRNA knock-down of 10 DUBs including USP20, UCLH5, and USP3 reduce the efficiency of DSB repair 67 . 63 Despite these interesting pre-clinical observations, the clear clinical settings for application of DUB inhibitors in cancer has yet to emerge.…”

Section: Ddr Regulation By Ubiquitin Like Phosphorylation Ubiquitinmentioning

confidence: 99%

Therapeutic opportunities within the DNA damage response

et al. 2015

View full text Add to dashboard Cite

The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell and its disruption is one of the 'Hallmarks of Cancer'. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer by radiation therapies or by genotoxic chemotherapies. More recently, protein components of the DDR systems are being identified as promising avenues for targeted cancer therapeutics. Here we present an in-depth analysis of the function, disease role and therapeutic potential of ~450 expert-curated human DDR genes. We discuss the current state of DDR drugs both FDA approved or under clinical investigation. We examine large-scale genomic and expression data in 15 cancers to identify deregulated components of the DDR in these tumours, and we apply systematic computational analysis to identify DDR proteins amenable to modulation by small molecules, highlighting potential novel therapeutic targets. 3The DNA Damage Response (DDR) evolved in response to the exposure of the genome to exogenous and endogenous genotoxins. Unless repaired in an error-free process, DNA damage can result in mutations and altered cellular behavior. Consequently, cells deploy a diverse repertoire of mechanisms to maintain genetic integrity 1 (see TABLE 1). These mechanisms involve the DNA repair processes themselves, the systems that regulate and organize them, and the systems that integrate DNA damage repair with the cell cycle 2 .Disruption of the DDR is observed in many cancers [3][4][5] , and underlies the genomic instability that accompanies tumourigenesis and progression. However, in the majority of cases, the specific underlying defects are poorly characterised 6,7 . Conversely, there are well-described cancers where disruption of a DDR mechanism is directly causal. In addition to these licensed drugs, there are a number of compounds currently under clinical evaluation that target DDR pathways directly. These targets include the protein kinases involved in cell cycle DNA checkpoint for DNA damage and/or replicative stress (eg CHEK1, WEE1), and individual enzymes involved in base excision repair (BER; APEX1), direct repair (MGMT), non-homologous DNA double strand break repair (NHEJ; PRKDC / DNA-PK) and telomere maintenance (TM; TERT).The initial rationale for development of DDR enzyme-targeted drugs focused on their use as potentiators, inhibiting repair of damage caused by radiotherapy and/or conventional genotoxins 11 .However, this approach has been extended to stand-alone use, targeting DNA repair pathways critical to tumour survival by exploiting synthetic sensitivity/lethality 16 (SSL). SSL arises when a combination of loss-of-function in two or more genes leads to cell death, while loss-of-function in only one of them does not. The therapeutic aim is to exploit genetic defects essential to a tumour's survival by combining the defect in an affected pathway with a pharmacologically induced defect in a compensating pathway 17 . 4The best example to date is the pharmaceutical inhibition...

show abstract

Deubiquitylating Enzymes and DNA Damage Response Pathways

Cited by 81 publications

References 208 publications

Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer

Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer

Regulation of USP28 Deubiquitinating Activity by SUMO Conjugation

Therapeutic opportunities within the DNA damage response

Contact Info

Product

Resources

About