Ttrap is an essential modulator of Smad3-dependent Nodal signaling during zebrafish gastrulation and left-right axis determination

Esguerra, Camila V.; Nelles, Luc; Vermeire, Liesbeth; Ibrahimi, Abdelilah; Crawford, Alexander D.; Derua, Rita; Janssens, Els; Waelkens, Etienne; Carmeliet, Peter; Collen, Désiré; Huylebroeck, Danny

doi:10.1242/dev.000026

Cited by 41 publications

(46 citation statements)

References 95 publications

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“…Recently, a modulator of Nodal signaling, Ttrap (32), and a mediator of Wnt signaling, duboraya (16), were shown to be involved in the establishment of laterality. Their loss-of-function phenotypes are similar to those of ier2 and fibp1, affecting cell movements and causing notochord undulation; in addition, duboraya is required for ciliogenesis in Kupffer's vesicle.…”

Section: Discussionmentioning

confidence: 99%

“…Failure of Organ Laterality in ier2 and fibp1 Morphants. Because of the association of convergent extension and laterality defects (16,32), we investigated the establishment of L/R asymmetry in embryos injected with ier2 or fibp1 MO. Severe deficits in laterality were observed after injection of either MO at high dose or a combination of the two MOs at low doses (Fig.…”

Section: B D E-l)mentioning

confidence: 99%

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FGF-dependent left–right asymmetry patterning in zebrafish is mediated by Ier2 and Fibp1

Hong

Dawid

2009

Proc. Natl. Acad. Sci. U.S.A.

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Establishment of left-right asymmetry in vertebrates requires nodal, Wnt-PCP and FGF signaling and involves ciliogenesis in a laterality organ. Effector genes through which FGF signaling affects laterality have not been described. We isolated the zebrafish ier2 and fibp1 genes as FGF target genes and show that their protein products interact. Knock down of these factors interferes with establishment of organ laterality and causes defective cilia formation in Kupffer's Vesicle, the zebrafish laterality organ. Cilia are also lost after suppression of FGF8, but can be rescued by injection of ier2 and fibp1 mRNA. We conclude that Ier2 and Fibp1 mediate FGF signaling in ciliogenesis in Kupffer's Vesicle and in the establishment of laterality in the zebrafish embryo.ciliogenesis ͉ Kupffer's vesicle ͉ laterality

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Section: Discussionmentioning

confidence: 99%

Section: B D E-l)mentioning

confidence: 99%

FGF-dependent left–right asymmetry patterning in zebrafish is mediated by Ier2 and Fibp1

Hong

Dawid

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Since TDP1 and TTRAP are complementary activities, together providing cells with an ability to remove trapped topoisomerase from both 3'-and 5'-DNA termini, we suggest that TTRAP be additionally designated Tyrosyl DNA Phosphodiesterase-2 (TDP2). It will now be of interest to determine how the tyrosyl DNA phosphodiesterase activity of TTRAP/TDP2 relates to the reported involvement of this protein in transcriptional regulation, apoptosis, and embryonic development 13,[22][23][24] . Given the central role fulfilled by topoisomerases in chromosome metabolism, our findings suggest that TTRAP/TDP2 may have additional important functions in many aspects of cell biology, including the suppression of chromosome instability and cancer.…”

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confidence: 99%

TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function

et al. 2014

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Here, we identify such an enzyme in human cells and show that this activity efficiently restores 5'-phosphate termini at DNA double-strand breaks in preparation for DNA ligation. We reveal that this enzyme is TTRAP, a member of the Mg 2+ /Mn 2+ -dependent family of phosphodiesterases, and show that cellular depletion of TTRAP results in increased susceptibility and sensitivity to topoisomerase II-induced DNA double-strand breaks. TTRAP is the first human 5'-tyrosine phosphodiesterase to be identified and we suggest this enzyme additionally be denoted tyrosyl DNA phosphodiesterase-2 (TDP2).In an attempt to identify novel human tyrosyl DNA phosphodiesterase activities, we exploited the hypersensitivity of Saccharomyces cerevisiae tdp1Δ rad1Δ double mutant cells to camptothecin (CPT), a topoisomerase I (Top1) poison that induces single-strand breaks (SSBs) with Top1 covalently linked to the 3'-terminus 3, 10 . This strain lacks not only Tdp1 but also Rad1-Rad10 nuclease, which in yeast provides an alternative (endonucleolytic) pathway for removing Top1 from 3'-termini 11,12 . We transformed this strain with a human cDNA library 3 and screened the resulting population of transformants for cellular resistance to CPT. Of six tdp1Δ rad1Δ transformants displaying wild-type levels of CPT resistance, three harboured cDNA clones encoding TDP1 and three harboured cDNA clones encoding TTRAP (TRAF and TNF receptor-associated protein), a protein of unknown function and a putative member of the Mg 2+ /Mn 2+ -dependent phosphodiesterase super-family, with the DNA repair protein AP endonuclease-1 (APE1) being its closest relative 13,14 (Fig.1a and Supplementary Fig.1).The TDP1 and TTRAP cDNA clones recovered in the genetic screen suppressed the CPT sensitivity of tdp1Δ rad1Δ cells to a similar extent (Fig. 1b & data not shown). Whilst the pACT-TTRAP clones encoded TTRAP protein that lacked eight (pACT-TTRAP-2, pACT-TTRAP-3) or twenty-two (pACT-TTRAP-1) residues from the amino-terminus (data not shown), full-length TTRAP similarly suppressed the CPT sensitivity of tdp1Δ rad1Δ (Fig. 1c, left). In contrast, human APE1 protein failed to suppress this sensitivity, suggesting that ability to complement CPT sensitivity in tdp1Δ rad1Δ cells is not a generic feature of metaldependent phosphodiesterases (Fig. 1c, left). Conversely, whereas human APE1 suppressed the sensitivity of AP endonuclease-defective apn1Δapn2Δ tpp1Δ yeast cells to methyl methanesulphonate (MMS)-induced DNA base damage, human TTRAP did not, suggesting that the impact of TTRAP in these experiments was restricted to topoisomerase-mediated DNA damage ( Fig. 1c, right). TTRAP contains four highly conserved motifs that putatively assign this protein to the metal-dependent phosphodiesterase superfamily (see Fig.1a and Supplementary Fig.1). We thus examined whether mutation of two predicted catalytic residues (Fig.1a; E152 and D262) within two of these motifs impacted on the complementation of CPT sensitivity by TTRAP. Indeed, in contrast to wild-type TTRAP protein, ne...

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“…3 Furthermore, TTRAP was isolated as ETS-associated protein II 4 and as alk4-and smad3-binding protein. 5 Interestingly, TTRAP sequence contains a SUMO-interacting motif (SIM) that is required for its high affinity binding to SUMO-2/3. 6 TTRAP may thus has a role in the cytoplasm as a signaling molecule and in the nucleus as a DNA damage response protein and transcriptional regulator.…”

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confidence: 99%

The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition

et al. 2011

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TRAF and TNF receptor-associated protein (TTRAP) is a multifunctional protein that can act in the nucleus as a 5 0 -tyrosyl DNA phosphodiesterase and in the cytoplasm as a regulator of cell signaling. In this paper we show that in response to proteasome inhibition TTRAP accumulates in nucleolar cavities in a promyelocytic leukemia protein-dependent manner. In the nucleolus, TTRAP contributes to control levels of ribosomal RNA precursor and processing intermediates, and this phenotype is independent from its 5 0 -tyrosyl DNA phosphodiesterase activity. Our findings suggest a previously unidentified function for TTRAP and nucleolar cavities in ribosome biogenesis under stress. Cell Death and Differentiation (2012) 19, 488-500; doi:10.1038/cdd.2011; published online 16 September 2011 TRAF and TNF receptor-associated protein (TTRAP) is a 5 0 -tyrosyl DNA phosphodiesterase that is required for the repair of topoisomerase2-induced DNA double-strand breaks. 1 It is a member of the endonuclease/exonuclease/ phosphatase family of proteins containing an Mg(2 þ )-dependent apurinic/apyrimidinic endonuclease Ape1-like domain. 2 Various yeast-two hybrid (Y2H) screenings and functional studies have unveiled TTRAP ability to interact with TNF receptors (TNFR) family members and TNFR-associated factors (TRAFs), especially TRAF6. 3 Furthermore, TTRAP was isolated as ETS-associated protein II 4 and as alk4-and smad3-binding protein. 5 Interestingly, TTRAP sequence contains a SUMO-interacting motif (SIM) that is required for its high affinity binding to SUMO-2/3. 6 TTRAP may thus has a role in the cytoplasm as a signaling molecule and in the nucleus as a DNA damage response protein and transcriptional regulator. In this context, its potential interaction with promyelocytic leukemia protein (PML), as previously determined in Y2H, suggests that TTRAP is a PML nuclear bodies (PML-NBs)-associated protein. 7 It remains unclear whether its 5 0 -tyrosyl DNA phosphodiesterase activity may account for all TTRAP biological functions.According to the cellular context, TTRAP may either protect cells from apoptosis or promote death. [8][9][10] When human SH-SY5Y cells are stressed by low doses of proteasome inhibitors, TTRAP is neuroprotective. In these conditions, endogenous TTRAP relocalizes to the cytoplasm and forms aggresome-like inclusions.In this paper we show that in response to high doses of proteasome inhibitors, TTRAP localizes to the nucleolus. This accumulation requires the association to PML-NBs and occurs in nucleolar cavities, a compartment devoid of markers of the 'ribosomal nucleolus'. Lack of TTRAP alters the levels of precursor ribosomal RNA (pre-rRNA) and processing intermediates, suggesting a new role of the PML-NBs-associated protein TTRAP in rRNA biogenesis. This function is dependent on TTRAP SIM motif, but is independent from its 5 0 -tyrosyl DNA phosphodiesterase activity. Altogether, these data suggest a novel function for TTRAP and nucleolar cavities in controlling rRNA biogenesis in response to proteasome inhibiti...

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Ttrap is an essential modulator of Smad3-dependent Nodal signaling during zebrafish gastrulation and left-right axis determination

Cited by 41 publications

References 95 publications

FGF-dependent left–right asymmetry patterning in zebrafish is mediated by Ier2 and Fibp1

FGF-dependent left–right asymmetry patterning in zebrafish is mediated by Ier2 and Fibp1

TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function

The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition

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