Tankyrase-Binding Protein TNKS1BP1 Regulates Actin Cytoskeleton Rearrangement and Cancer Cell Invasion

Ohishi, Tomokazu; Yoshida, Haruka; Katori, Masamichi; Migita, Toshiro; Muramatsu, Yukiko; Miyake, Mao; Ishikawa, Yuichi; Saiura, Akio; Iemura, Shun‐ichiro; Natsume, Tohru; Seimiya, Hiroyuki

doi:10.1158/0008-5472.can-16-1846

Cited by 36 publications

(39 citation statements)

References 54 publications

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“…By contrast, we did not observe downregulation of MERIT40 in tankyrase-overexpressing cells (Figure 3A ). This would be reminiscent of TNKS1BP1, another tankyrase-binding protein, which is PARsylated by tankyrase but not downregulated in tankyrase-overexpressing cells [ 10 , 27 ]. One possibility is that PAR chains in the tankyrase-MERIT40 complexes work as a scaffold to promote DNA repair as PARP-1/2-derived PAR chains play such a role.…”

Section: Discussionmentioning

confidence: 99%

MERIT40-dependent recruitment of tankyrase to damaged DNA and its implication for cell sensitivity to DNA-damaging anticancer drugs

et al. 2018

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Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, regulates various intracellular responses, such as telomere maintenance, Wnt/β-catenin signaling and cell cycle progression through its interactions with multiple target proteins. Tankyrase contains a long stretch of 24 ankyrin repeats that are further divided into five subdomains, called ANK repeat clusters (ARCs). Each ARC works as an independent ligand-binding unit, which implicates tankyrase as a platform for multiple protein-protein interactions. Furthermore, tankyrase distributes to various intracellular loci, suggesting potential distinct but yet unidentified physiological functions. To explore the novel functions of tankyrase, we performed liquid chromatography-mass spectrometry analysis and identified the BRE-BRCC36-MERIT40 complex, a regulator of homologous recombination, as tankyrase-binding proteins. Among the complex components, MERIT40 was directly associated with tankyrase via a tankyrase-binding consensus motif, as previously reported. In X-ray-irradiated non-small cell lung cancer cells, tankyrase localized to DNA double-stranded break sites in a MERIT40-dependent manner. MERIT40 knockdown increased the cell sensitivity to X-ray, whereas the wild-type, but not the tankyrase-unbound mutant, MERIT40 rescued the phenotype of the knockdown cells. Tankyrase inhibitors, such as G007-LK and XAV939, increased the cellular sensitivity to X-ray irradiation and anticancer drugs that induce DNA double-stranded breaks. These observations suggest that tankyrase plays a role in the DNA damage repair response and implicates a potential therapeutic utility of tankyrase inhibitors in combination treatments with DNA-damaging anticancer drugs.

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Section: Discussionmentioning

confidence: 99%

MERIT40-dependent recruitment of tankyrase to damaged DNA and its implication for cell sensitivity to DNA-damaging anticancer drugs

et al. 2018

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“…It appears to be required for efficient DSB repair and facilitates the poly(ADP-ribose) polymerase 1 (PARP1)-dependent autophosphorylation of DNA-PK, although its precise role is not clear at present ( 34 , 35 ; our unpublished data). In addition, Tab182 has a role in the regulation of the actin cytoskeleton ( 36 ). Tab182 was previously suggested to be a component of the mammalian CNOT complex, although its role in this context is unknown.…”

Section: Introductionmentioning

confidence: 99%

Degradation of a Novel DNA Damage Response Protein, Tankyrase 1 Binding Protein 1, following Adenovirus Infection

Hagkarim

Ryan

Byrd

et al. 2018

J Virol

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Infection by most DNA viruses activates a cellular DNA damage response (DDR), which may be to the detriment or advantage of the virus. In the case of adenoviruses, they neutralize antiviral effects of DDR activation by targeting a number of proteins for rapid proteasome-mediated degradation. We have now identified a novel DDR protein, tankyrase 1 binding protein 1 (TNKS1BP1) (also known as Tab182), which is degraded during infection by adenovirus serotype 5 and adenovirus serotype 12. In both cases, degradation requires the action of the early region 1B55K (E1B55K) and early region 4 open reading frame 6 (E4orf6) viral proteins and is mediated through the proteasome by the action of cullin-based cellular E3 ligases. The degradation of Tab182 appears to be serotype specific, as the protein remains relatively stable following infection with adenovirus serotypes 4, 7, 9, and 11. We have gone on to confirm that Tab182 is an integral component of the CNOT complex, which has transcriptional regulatory, deadenylation, and E3 ligase activities. The levels of at least 2 other members of the complex (CNOT3 and CNOT7) are also reduced during adenovirus infection, whereas the levels of CNOT4 and CNOT1 remain stable. The depletion of Tab182 with small interfering RNA (siRNA) enhances the expression of early region 1A proteins (E1As) to a limited extent during adenovirus infection, but the depletion of CNOT1 is particularly advantageous to the virus and results in a marked increase in the expression of adenovirus early proteins. In addition, the depletion of Tab182 and CNOT1 results in a limited increase in the viral DNA level during infection. We conclude that the cellular CNOT complex is a previously unidentified major target for adenoviruses during infection.IMPORTANCE Adenoviruses target a number of cellular proteins involved in the DNA damage response for rapid degradation. We have now shown that Tab182, which we have confirmed to be an integral component of the mammalian CNOT complex, is degraded following infection by adenovirus serotypes 5 and 12. This requires the viral E1B55K and E4orf6 proteins and is mediated by cullin-based E3 ligases and the proteasome. In addition to Tab182, the levels of other CNOT proteins are also reduced during adenovirus infection. Thus, CNOT3 and CNOT7, for example, are degraded, whereas CNOT4 and CNOT1 are not. The siRNA-mediated depletion of components of the complex enhances the expression of adenovirus early proteins and increases the concentration of viral DNA produced during infection. This study highlights a novel protein complex, CNOT, which is targeted for adenovirus-mediated protein degradation. To our knowledge, this is the first time that the CNOT complex has been identified as an adenoviral target.

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“…Thus, we identified 25 RBPs (Fig. 6B): 5 never studied in cancer (CSTF2T, SRRM1, CPSF7, EIF4G3, and ELOA), 6 associated with other cancer types (TNRC6B 62 , SEC31A 63 , SPTAN1 64 , MARK2 65 , TNRC6A 66 , and PMS1 67 ), 7 associated with BC (CASC3 68 , HNRNPF 69 , MYH9 70 TLN1 71 , DDX5 72 , TAF15 73 , and EIF4G1 74 ), 3 already described as tumor suppressors in BC (CTNND1 23 , LIMA1 24 , AATF 25 ), and 4 identified as tumor suppressors in other cancer types (MEX3C 75 , UPF1 76 , CNOT1 77 , and TNKS1BP1 78 ).…”

Section: Resultsmentioning

confidence: 99%

“…Although most of the proteins identified have been associated with breast and other cancer types, their suppressive roles remain undetermined 62–74 . Only 3 have been described as tumor suppressors in BC (CTNND1 23 , LIMA1 24 , AATF 25 ), and 4 has been identified as tumor suppressors in other cancer types (MEX3C 75 , UPF1 76 , CNOT1 77 , and TNKS1BP1 78 ). Interestingly, 5 have never been studied in cancer: CSTF2T, SRRM1, CPSF7, EIF4G3, and ELOA.…”

Section: Discussionmentioning

confidence: 99%

In silico analyses reveal new putative Breast Cancer RNA-binding proteins

Guerrero

López‐Cortés

García-Cárdenas

et al. 2020

Preprint

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Breast cancer (BC) is the leading cause of cancer-associated death among women worldwide. Despite treatment efforts, advanced BC with distant organ metastases is considered incurable. A better understanding of BC molecular processes is therefore of great interest to identify new therapeutic targets. Although large-scale efforts, such as The Cancer Genome Atlas (TCGA), have completely redefined cancer drug development, diagnosis, and treatment, additional key aspects of tumor biology remain to be discovered. In that respect, post-transcriptional regulation of tumorigenesis represents an understudied aspect of cancer research. As key regulators of this process, RNA-binding proteins (RBPs) are emerging as critical modulators of tumorigenesis but only few have defined roles in BC. To unravel new putative BC RBPs, we have performed in silico analyses of all human RBPs in three major cancer databases (TCGA-Breast Invasive Carcinoma, the Human Protein Atlas, and the Cancer Dependency Map project) along with complementary bioinformatics resources (STRING protein-protein interactions and the Network of Cancer Genes 6.0). Thus, we have identified six putative BC progressors (MRPL13, SCAMP3, CDC5L, DARS2, PUF60, and PLEC), and five BC suppressors RBPs (SUPT6H, MEX3C, UPF1, CNOT1, and TNKS1BP1). These proteins have never been studied in BC but show similar cancer-associated features than well-known BC proteins. Further research should focus on the mechanisms by which these proteins promote or suppress breast tumorigenesis, holding the promise of new therapeutic pathways along with novel drug development strategies.

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Tankyrase-Binding Protein TNKS1BP1 Regulates Actin Cytoskeleton Rearrangement and Cancer Cell Invasion

Cited by 36 publications

References 54 publications

MERIT40-dependent recruitment of tankyrase to damaged DNA and its implication for cell sensitivity to DNA-damaging anticancer drugs

MERIT40-dependent recruitment of tankyrase to damaged DNA and its implication for cell sensitivity to DNA-damaging anticancer drugs

Degradation of a Novel DNA Damage Response Protein, Tankyrase 1 Binding Protein 1, following Adenovirus Infection

In silico analyses reveal new putative Breast Cancer RNA-binding proteins

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