Ubiquitin-specific Peptidase 20 Regulates Rad17 Stability, Checkpoint Kinase 1 Phosphorylation and DNA Repair by Homologous Recombination

Shanmugam, Ilanchezhian; Abbas, Mohammad; Ayoub, Farhan; Mirabal, Susan; Bsaili, Manal; Caulder, Erin K.; Weinstock, David M.; Tomkinson, Alan E.; Hromas, Robert; Shaheen, Monte

doi:10.1074/jbc.m114.550459

Cited by 28 publications

(27 citation statements)

References 21 publications

(24 reference statements)

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“…This is consistent with the observation by Shaheen et al. (31). Given that USP20 depletion-induced promotion of CHK1 activation is rescued by overexpression of CLASPIN (Figure 2H), CLASPIN is the major substrate for USP20 in CHK1 activation.…”

Section: Resultsmentioning

confidence: 99%

HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability

Zhu

Zhao

Liao

et al. 2014

Nucleic Acids Research

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CLASPIN is an essential mediator in the DNA replication checkpoint, responsible for ATR (ataxia telangiectasia and Rad3-related protein)-dependent activation of CHK1 (checkpoint kinase 1). Here we found a dynamic signaling pathway that regulates CLASPIN turn over. Under unperturbed conditions, the E3 ubiquitin ligase HERC2 regulates the stability of the deubiquitinating enzyme USP20 by promoting ubiquitination-mediated proteasomal degradation. Under replication stress, ATR-mediated phosphorylation of USP20 results in the disassociation of HERC2 from USP20. USP20 in turn deubiquitinates K48-linked-polyubiquitinated CLASPIN, stabilizing CLASPIN and ultimately promoting CHK1 phosphorylation and CHK1-directed checkpoint activation. Inhibition of USP20 expression promotes chromosome instability and xenograft tumor growth. Taken together, our findings demonstrated a novel function of HERC2/USP20 in coordinating CHK1 activation by modulating CLASPIN stability, which ultimately promotes genome stability and suppresses tumor growth.

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Section: Resultsmentioning

confidence: 99%

HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability

Zhu

Zhao

Liao

et al. 2014

Nucleic Acids Research

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“…Currently, a study found that the high frequency of the 3-bp deletion in the USP20 gene in Korean population, which mean a biased susceptibility of Korean individuals to certain cancer types, and the potential mechanisms of carcinogenesis caused by mutant USP20 are still unknown (20). Furthermore, searching public databases of the Sanger Cosmic and the Cancer Genome Atlas, frequent point mutations and deletions of USP20 are found to exist in a variety of malignancies (13). Moreover, USP20 has been confirmed involved in various cellular mechanisms by impeding Tax- and interleukin 1p (IL-1p)-induced NF-κB activation by targeting Tax and TRAF6 for deubiquitination, which results in slower cell growth in ATL2 cells (14), enhancing HIF-1α-induced hypoxia response element (HRE) luciferase activity and VEGF protein expression via salvaging ubiquitinated HIF-1α from proteasomal degradation (12), and regulating β2 adrenergic receptor (β2AR) recycling and resensitization (21).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, USP20 has been confirmed involved in various cellular mechanisms by impeding Tax- and interleukin 1p (IL-1p)-induced NF-κB activation by targeting Tax and TRAF6 for deubiquitination, which results in slower cell growth in ATL2 cells (14), enhancing HIF-1α-induced hypoxia response element (HRE) luciferase activity and VEGF protein expression via salvaging ubiquitinated HIF-1α from proteasomal degradation (12), and regulating β2 adrenergic receptor (β2AR) recycling and resensitization (21). As Rad17 was implicated in carcinogenesis as a tumor suppresser gene that play a role in a haplo-insufficient manner (22), and USP20 stabilized Rad17 in a proteasome-dependent manner, USP20 itself was considered as a novel tumor suppressor protein (13). Additionally, USP20 could be ubiquitinated in a pVHL-dependent manner, inducing itself rapid degradation (23).…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinating enzyme USP20 is a positive regulator of claspin and suppresses the malignant characteristics of gastric cancer cells

Wang

Yang

et al. 2017

International Journal of Oncology

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The aim of the present study was to investigate the clinical significance, the biological function and the mechanisms of USP20 in gastric cancer. The expression of USP20 in 89 pairs of primary gastric cancer and peritumoral gastric tissues specimens were measured by immunohistochemistry. The correlation of USP20 expression with the survival and the clinicopathological characteristics of patients were analyzed. Moreover, the underlying mechanisms of ectopic USP20 expression and its impact on GC cells were also investigated. We found that the expression of USP20 is relatively low in GC tissues and negatively correlated with tumor size, tumor invasion and TNM staging. High expression of USP20 in GC predicted longer survival. Experimentally, small interfering RNA-mediated knockdown of USP20 expression significantly promoted cell proliferation, accelerated G1-S phase transition and attenuated the autophagy activity. Overexpression of USP20 led to the inhibition of proliferation, G1-S cell cycle transition delay and autophagy activation. Mechanistically, we confirmed that silencing the expression of USP20 in GC cells could reduce Claspin protein levels without altering Claspin mRNA levels, which is involved in the antitumor activity of USP20. Furthermore, the expression level of Claspin was relatively higher in peritumoral tissue than that of GC tissues and higher expression of Claspin in GC was also correlated with good prognosis of patients. Given its pivotal role in gastric tumorigenesis and progression, USP20 functioned as the tumor suppressor in GC and possessed promising value to be a therapeutic target for GC.

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“…PKA-dependent phosphorylation of the DUB USP20 was recently shown to perturb post-endocytic trafficking of the β-andregenic receptor under cellular stress conditions. USP20 is implicated in control of the DNA damage response, cell cycling, and NF-κB activity 168, 169 , and its regulation by PKA links this kinase to control of DNA damage and NF-κB activity.…”

Section: Regulation By Alternative Splicingmentioning

confidence: 99%

Dysregulation of ubiquitin ligases in cancer

Ronai

2015

Drug Resistance Updates

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Ubiquitin ligases are critical components of the ubiquitin proteasome system (UPS), which governs fundamental processes regulating normal cellular homeostasis, metabolism, and cell cycle in response to external stress signals and DNA damage. Among multiple steps of the UPS system required to regulate protein ubiquitination and stability, UBLs define specificity, as they recognize and interact with substrates in a temporally- and spatially-regulated manner. Such interactions are required for substrate modification by ubiquitin chains, which marks proteins for recognition and degradation by the proteasome, or alters their subcellular localization or assembly into functional complexes. UBLs are often deregulated in cancer, altering substrate availability or activity in a manner that can promote cellular transformation. Such deregulation can occur at the epigenetic, genomic, or post-translational levels. Alterations in UBL can be used to predict their contributions, affecting tumor suppressors or oncogenes in select tumors. Better understanding of mechanisms underlying UBL expression and activities is expected to drive the development of next generation modulators that can serve as novel therapeutic modalities. This review summarizes our current understanding of UBL deregulation in cancer and highlights novel opportunities for therapeutic interventions.

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Ubiquitin-specific Peptidase 20 Regulates Rad17 Stability, Checkpoint Kinase 1 Phosphorylation and DNA Repair by Homologous Recombination

Cited by 28 publications

References 21 publications

HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability

HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability

Deubiquitinating enzyme USP20 is a positive regulator of claspin and suppresses the malignant characteristics of gastric cancer cells

Dysregulation of ubiquitin ligases in cancer

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