http://www.cnr.it/ontology/cnr/individuo/prodotto/ID27207

Transcription-associated breaks in xeroderma pigmentosum group D cells from patients with combined features of xeroderma pigmentosum and Cockayne Syndrome. (Articolo in rivista)

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Transcription-associated breaks in xeroderma pigmentosum group D cells from patients with combined features of xeroderma pigmentosum and Cockayne Syndrome. (Articolo in rivista) (literal)

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Theron T., Fousteri M.I., Volker M., Harries L.W., Botta E., Stefanini M., Fujimoto M., Andressoo J., Mitchell J., Jaspers N.G.J., McDaniel L.D., Mullenders L. and Lehmann A.R. (2005)
Transcription-associated breaks in xeroderma pigmentosum group D cells from patients with combined features of xeroderma pigmentosum and Cockayne Syndrome.
in Molecular and cellular biology (Print); ASM, American society for microbiology, Washington, DC (Stati Uniti d'America)
(literal)

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Theron T., Fousteri M.I., Volker M., Harries L.W., Botta E., Stefanini M., Fujimoto M., Andressoo J., Mitchell J., Jaspers N.G.J., McDaniel L.D., Mullenders L. and Lehmann A.R. (literal)

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Questo studio ha permesso di chiarire le basi dell'anomalo fenotipo cellulare osservato unicamente in pazienti difettivi nel gene XPD che mostrano in associazione ai sintomi dello xeroderma pigmentosum (XP) alcuni dei sintomi tipici della sindrome di Cockayne (CS). Nelle cellule di questi pazienti è presente un'attività di monitoraggio del danno che determina l'incisione della molecola di DNA in siti lontani dalla lesione. Questo spiega perchè le cellule XP/CS mostrino unestrema sensibilità agli effetti letali della luce UV ma normale capacità di operare l'incisione dopo irradiazione. È stato definito che l'anomalo fenotipo cellulare delle cellule XP/CS mutate in XPD è dovuto al fatto che lapparativo riparativo coinvolto nella riparazione dei danni indotti da UV introduce delle rotture nei siti di inizio della trascrizione. (literal)

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Theron, Volker, Harries, Lehmann: Genome Damage and Stability Centre, University of Sussex, United Kingdom; Fousteri, Mullenders: MGC Dep. Toxicogenetics, Leiden University Medical Centre, Leiden, The Netherlands; Fujimoto: Department of Dermatology, Jichi Medical School, Minami-kawachi-machi, Japan; Andressoo, Mitchell, Jaspers: MGC, Department of Cell Biology and Genetics, Erasmus University MC, Rotterdam, The Netherlands; McDaniel: Department of Pathology, UT Southwestern Medical, Dallas, Texas Botta, Stefanini: IGM-CNR, Pavia. (literal)

Titolo

Transcription-associated breaks in xeroderma pigmentosum group D cells from patients with combined features of xeroderma pigmentosum and Cockayne Syndrome. (literal)

Abstract

Defects in the XPD gene can result in several clinical phenotypes, including xeroderma pigmentosum (XP), trichothiodystrophy, and, less frequently, the combined phenotype of XP and Cockayne syndrome (XP-D/CS). We previously showed that in cells from two XP-D/CS patients, breaks were introduced into cellular DNA on exposure to UV damage, but these breaks were not at the sites of the damage. In the present work, we show that three further XP-D/CS patients show the same peculiar breakage phenomenon. We show that these breaks can be visualized inside the cells by immunofluorescence using antibodies to either gamma-H2AX or poly-ADP-ribose and that they can be generated by the introduction of plasmids harboring methylation or oxidative damage as well as by UV photoproducts. Inhibition of RNA polymerase II transcription by four different inhibitors dramatically reduced the number of UV-induced breaks. Furthermore, the breaks were dependent on the nucleotide excision repair (NER) machinery. These data are consistent with our hypothesis that the NER machinery introduces the breaks at sites of transcription initiation. During transcription in UV-irradiated XP-D/CS cells, phosphorylation of the carboxy-terminal domain of RNA polymerase II occurred normally, but the elongating form of the polymerase remained blocked at lesions and was eventually degraded. (literal)

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