Ku autoantigen is the regulatory component of a template-associated protein kinase that phosphorylates RNA polymerase II.

Dvir, Arik; Peterson, Scott; Knuth, Mark W.; Lu, Hua; Dynan, William S.

doi:10.1073/pnas.89.24.11920

Cited by 376 publications

(299 citation statements)

References 54 publications

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“…Nascent RNAP II transcripts have been found to occur in association with small nuclear ribonucleoproteins, including the U1RNP particle [38]. The Ku autoantigen was shown to be the regulatory component of the kinase complex responsible for phosphorylated RNAP IIA to form RNAP IIO [39]. Finally, there is the recent identification of topo I as a transcription factor for RNAP IItranscribed genes [26].…”

Section: Discussionmentioning

confidence: 99%

Anti-RNA polymerase antibodies in systemic sclerosis (SSc): association with anti-topoisomerase I antibodies and identification of autoreactive subunits of RNA polymerase II

Harvey

Rands

McHugh

1996

Clinical and Experimental Immunology

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SUMMARYThe prevalence of autoantibodies to the three RNA polymerase (RNAP) enzymes in the sera of 249 SSc patients was measured using the technique of immunoprecipitation of 35 S-methionine-labelled K562 cell extracts. Forty-six anti-RNAP sera were detected (18 . 5%) and three main groups were identified: anti-RNAP I/III sera (10; 4 . 0%), anti-RNAP I/II/III sera (15; 6 . 0%), and sera precipitating the phosphorylated (IIO) form of RNAP II (18; 7 . 2%). All sera in the third group also precipitated topoisomerase I (topo I), and six of them also precipitated the unphosphorylated (IIA) form of RNAP II. Although RNAP II/topo I multienzyme complexes may occur in cell extracts, autoreactive epitopes were shown to be located on both enzymes by a combination of antigen depletion studies, and in vitro assays which demonstrated functional inhibition of topo I activity. Furthermore, immunoblotting experiments using affinity-purified extracts demonstrated that all sera with anti-RNAP II antibodies recognized the largest RNAP II subunit in its phosphorylated form (IIo; 240 kD), whereas the unphosphorylated subunit (IIa; 220 kD) was only recognized by sera which also precipitated RNAP IIA. Therefore at least two different sites on the largest subunit of RNAP II are recognized by SSc sera, and one of these sites is unique to the phosphorylated (IIO) form.

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Section: Discussionmentioning

confidence: 99%

Anti-RNA polymerase antibodies in systemic sclerosis (SSc): association with anti-topoisomerase I antibodies and identification of autoreactive subunits of RNA polymerase II

Harvey

Rands

McHugh

1996

Clinical and Experimental Immunology

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“…In fact, DNA-PK inhibitors, such as wortmannin and LY297004, inhibit each of these enzymes. The DNA-PK complex is composed of Ku80, Ku70, and the DNAPKcs (7)(8)(9)(10). Ku80 and Ku70 bind to DNA DSB to facilitate the binding of and perhaps the activation of DNA-PKcs.…”

Section: Introductionmentioning

confidence: 99%

DNA-Dependent Protein Kinase Is a Molecular Target for the Development of Noncytotoxic Radiation–Sensitizing Drugs

et al. 2005

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DNA-dependent protein kinase (DNA-PK)-defective severe combined immunodeficient (SCID) mice have a greater sensitivity to ionizing radiation compared with wild-type mice due to deficient repair of DNA double-strand break. SCID cells were therefore studied to determine whether radiosensitization by the specific inhibitor of DNA-PK, IC87361, is eliminated in the absence of functional DNA-PK. IC87361 enhanced radiation sensitivity in wild-type C57BL6 endothelial cells but not in SCID cells. The tumor vascular window model was used to assess IC87361-induced radiosensitization of SCID and wild-type tumor microvasculature. Vascular density was 5% in irradiated SCID host compared with 50% in C57BL6 mice (P < 0.05). IC87361 induced radiosensitization of tumor microvasculature in wild-type mice that resembled the radiosensitive phenotype of tumor vessels in SCID mice. Radiosensitization by IC87361 was eliminated in SCID tumor vasculature, which lack functional DNA-PK. Irradiated LLC and B16F0 tumors implanted into SCID mice showed greater tumor growth delay compared with tumors implanted into either wild-type C57BL6 or nude mice. Furthermore, LLC tumors treated with radiation and IC87361 showed tumor growth delay that was significantly greater than tumors treated with radiation alone (P < 0.01 for 3 Gy alone versus 3 Gy + IC87361). DNA-PK inhibitors induced no cytotoxicity and no toxicity in mouse normal tissues. Mouse models deficient in enzyme activity are useful to assess the specificity of novel kinase inhibitors. DNA-PK is an important target for the development of novel radiation-sensitizing drugs that have little intrinsic cytotoxicity. (Cancer Res 2005; 65(12): 4987-92)

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“…DNA-dependent protein kinase (DNA-PK) is composed of a 460-kDa catalytic subunit tentatively termed DNA-PKcs [1] and a DNA-binding component Ku protein (p70/p80) [2][3][4]. DNA-PK requires double-stranded DNA for the phosphorylation of a variety of replication/transcription factors, such as Spl, p53, c-Myc and RP-A [5][6][7][8][9][10][11][12][13], which likely contain X-S/ T-Q or P-S/T-X as minimal requirement for the recognition sequence [4].…”

Section: Introductionmentioning

confidence: 99%

CPP32/Yama/apopain cleaves the catalytic component of DNA‐dependent protein kinase in the holoenzyme

et al. 1996

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recently reported that several nuclear autoantigens including poly(ADP-ribose) polymerase, U1 snRNA-70 kDa and DNAPKcs are cleaved early during apoptosis in UV-irradiated HeLa cells. Poly(ADP-ribose) polymerase that seems to be involved in DNA repair has recently been reported to be a potential substrate for apopain, also called CPP32 or Yama, under the apoptotic process [24][25][26]. Since the human Jurkat T cell line exhibits typical apoptosis after treatment with Fas ligand or an agonistic anti-Fas antibody [27], we examined the possibility that DNA-PKcs is one of the death substrates during Fas-mediated apoptosis in the Jurkat T cell line.Here we show that DNA-PKcs was cleaved on incubation with recombinant apopain in vitro as well as during Fasmediated apoptosis in Jurkat cells.

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Ku autoantigen is the regulatory component of a template-associated protein kinase that phosphorylates RNA polymerase II.

Cited by 376 publications

References 54 publications

Anti-RNA polymerase antibodies in systemic sclerosis (SSc): association with anti-topoisomerase I antibodies and identification of autoreactive subunits of RNA polymerase II

Anti-RNA polymerase antibodies in systemic sclerosis (SSc): association with anti-topoisomerase I antibodies and identification of autoreactive subunits of RNA polymerase II

DNA-Dependent Protein Kinase Is a Molecular Target for the Development of Noncytotoxic Radiation–Sensitizing Drugs

CPP32/Yama/apopain cleaves the catalytic component of DNA‐dependent protein kinase in the holoenzyme

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