Human POMp75 is identified as the pro-oncoprotein TLS/FUS: both POMp75 and POMp100 DNA homologous pairing activities are associated to cell proliferation

Bertrand, Pascale; Akhmedov, Alexandre T.; Delacôte, Fabien; Dürrbach, Antoine; Lopez, Bernard S.

doi:10.1038/sj.onc.1203048

Cited by 79 publications

(71 citation statements)

References 64 publications

(59 reference statements)

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“…These data agree with a role of TLS in transcriptional regulation. TLS has been biochemically characterized as hPOMp75, a protein involved in homologous DNA pairing and recombination (Baechtold et al, 1999;Bertrand et al, 1999). This activity fits with the increased sensitivity to ionizing radiation due to chromosome pairing defects during meiosis in the TLS-deficient mice suggesting that TLS could participate to the maintenance of genomic integrity (Kuroda et al, 2000).…”

Section: Introductionmentioning

confidence: 85%

Multiple functional domains of the oncoproteins Spi-1/PU.1 and TLS are involved in their opposite splicing effects in erythroleukemic cells

et al. 2004

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The hematopoietic transcription factor Spi-1/PU.1 is an oncoprotein participating to the malignant transformation of proerythroblasts in the Friend erythroleukemia or in the erythroleukemic process developed in spi-1 transgenic mice. Overexpression of Spi-1 in proerythroblasts blocks their differentiation. We have shown that Spi-1 promotes the use of the proximal 5 0 -splice site during the E1A premRNA splicing and interferes with the effect of TLS (Translocated in LipoSarcoma) in this splicing assay. TLS was identified from chromosomal translocations in human liposarcoma and acute myeloid leukemia. Here, we determine the function of Spi-1 domains in splicing and in the interference with TLS. In transient transfection assays in erythroid cells, we show that the DNA binding domain cooperates with the transactivation domain or the PEST region of Spi-1 to modify the function of TLS in splicing. Interestingly, the 27 C-terminal amino acids, which determine the DNA binding activity of Spi-1, are necessary for the splicing function of Spi-1 as well as for its ability to interfere with TLS. Finally, we demonstrate that in leukemic proerythroblasts overexpressing Spi-1, TLS has lost its splicing effect. Thus, we hypothesize that oncogenic pathways in proerythroblasts may involve the ability of Spi-1 to alter splicing.

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Section: Introductionmentioning

confidence: 85%

Multiple functional domains of the oncoproteins Spi-1/PU.1 and TLS are involved in their opposite splicing effects in erythroleukemic cells

et al. 2004

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Section: Tls (Translocated In Liposarcoma)mentioning

confidence: 99%

“…Indeed, analysis of TLS-deficient mice suggests a possible role of TLS in both repairing DNA damage (12) and maintaining genomic integrity (13). According to these biological data, various biochemical studies identified TLS as a protein involved in pairing DNA sequences during homologous recombination (14,15).Other data argue for a role of TLS in regulation of gene transcription. TLS as EWS and the highly similar factor hTAFII 68 have been purified in distinct TFIID complexes associated with the RNA polymerase II (16,17).…”

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confidence: 99%

Identification of an RNA Binding Specificity for the Potential Splicing Factor TLS

Lerga

Hallier

Delva

et al. 2001

Journal of Biological Chemistry

166

170

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The TLS/FUS gene is involved in a recurrent chromosomal translocation in human myxoid liposarcomas. We previously reported that TLS is a potential splicing regulator able to modulate the 5-splice site selection in an E1A pre-mRNA. Using an in vitro selection procedure, we investigated whether TLS exhibits a specificity with regard to RNA recognition. The RNAs selected by TLS share a common GGUG motif. Mutation of a G or U residue within this motif abolishes the interaction of TLS with the selected RNAs. We showed that TLS can bind GGUG-containing RNAs with a 250 nM affinity. By UV cross-linking/competition and immunoprecipitation experiments, we demonstrated that TLS recognizes a GGUG-containing RNA in nuclear extracts. Each one of the RNA binding domains (the three RGG boxes and the RNA recognition motif) contributes to the specificity of the TLS⅐RNA interaction, whereas only RRM and RGG2-3 participate to the E1A alternative splicing in vivo. The specificity of the TLS⅐RNA interaction was also observed using as natural pre-mRNA, the G-rich IVSB7 intron of the ␤-tropomyosin pre-mRNA. Moreover, we determined that RNA binding specificities of TLS and high nuclear ribonucleoprotein A1 were different. Hence, our results help define the role of the specific interaction of TLS with RNA during the splicing process of a pre-mRNA. TLS (Translocated in LipoSarcoma)1 or FUS has been first characterized as a rearranged gene in chromosomal translocations specific of human myxoid liposarcoma (1, 2). The resulting fusion protein contains the N-terminal part of TLS fused to a transcription factor of the CAAT/enhancer-binding protein family of proteins: CHOP. In an acute myeloid leukemia, TLS is also involved in a chromosomal breakpoint that juxtaposes the same N-terminal region of TLS to a transcription factor of the ETS proteins family: ERG-1 (3, 4). TLS is highly similar to EWS, a gene implicated in chromosomal translocations that are specific of the tumors of the Ewing family (5, 6). In most of these sarcoma, the N-terminal region of EWS is fused to the DNA binding domain of either ERG-1 or FLI-1, which are two closely related ETS proteins.Both TLS and EWS have in common a similar structural organization. Their C terminus part contains multiple domains that are involved in RNA⅐protein interactions: an RNA recognition motif (RRM) flanked by two regions rich in Arg-Gly-Gly repeats (RGG domains) and a C 2 C 2 zinc finger. In their N terminus domain, they contain a glutamine-, serine-, and tyrosine-rich region that functions as a transcriptional activation domain when fused to a heterologous DNA binding domain (7-9). In oncogenic chimera, the adjunction of this N-terminal region of TLS or EWS to the transcriptional regulators CHOP, FLI-1, or ERG-1 generates proteins with transcriptional activities that differ from those of the wild-type counterpart (8,10). From these data it has been proposed that the oncogenic fusion proteins disturb the expression of genes that are regulated by CHOP, FLI-1, or ERG-1. However, no cellular targe...

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“…For example, a recent study has shown the involvement of hnRNPA1 in Okazaki fragment maturation during DNA replication as a stimulator of the FEN-1 nuclease (33). A novel role of another ribonucleoprotein, this time in genome maintenance, has also been demonstrated; the TLS/FUS protein has been shown to mediate homologous pairing and to be involved in the DNA damage response (34). The TASR (TLS-associated SR) proteins, identified as being involved in DPCs in our study, may also be involved in these processes because of their association with TLS.…”

Section: Discussionmentioning

confidence: 99%

Identification of Mammalian Proteins Cross-linked to DNA by Ionizing Radiation

Barker¹,

Weinfeld²,

Zheng

et al. 2005

Journal of Biological Chemistry

108

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Ionizing radiation (IR) is an important environmental risk factor for various cancers and also a major therapeutic agent for cancer treatment. Exposure of mammalian cells to IR induces several types of damage to DNA, including double-and single-strand breaks, base and sugar damage, as well as DNA-DNA and DNA-protein crosslinks (DPCs). Little is known regarding the biological consequences of DPCs. Identifying the proteins that become cross-linked to DNA by IR would be an important first step in this regard. We have therefore undertaken a proteomics study to isolate and identify proteins involved in IR-induced DPCs. DPCs were induced in AA8 Chinese hamster ovary or GM00637 human fibroblast cells using 0 -4 gray of ␥-rays under either aerated or hypoxic conditions. DPCs were isolated using a recently developed method, and proteins were identified by mass spectrometry. We identified 29 proteins as being cross-linked to DNA by IR under aerated and/or hypoxic conditions. The identified proteins include structural proteins, actin-associated proteins, transcription regulators, RNA-splicing components, stress-response proteins, cell cycle regulatory proteins, and GDP/GTP-binding proteins. The involvement of several proteins (actin, histone H2B, and others) in DPCs was confirmed by using Western blot analysis. The dose responsiveness of DPC induction was examined by staining one-dimensional SDS-polyacrylamide gels with SYPRO Tangerine followed by analysis using fluorescence imaging. Quantitation of the fluorescence signal indicated no significant difference in total yields of IR-induced DPCs generated under aerated or hypoxic conditions, although differences were observed for several individual protein bands.

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Human POMp75 is identified as the pro-oncoprotein TLS/FUS: both POMp75 and POMp100 DNA homologous pairing activities are associated to cell proliferation

Cited by 79 publications

References 64 publications

Multiple functional domains of the oncoproteins Spi-1/PU.1 and TLS are involved in their opposite splicing effects in erythroleukemic cells

Multiple functional domains of the oncoproteins Spi-1/PU.1 and TLS are involved in their opposite splicing effects in erythroleukemic cells

Identification of an RNA Binding Specificity for the Potential Splicing Factor TLS

Identification of Mammalian Proteins Cross-linked to DNA by Ionizing Radiation

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