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2. The human nucleoporin Tpr protects cells from RNA-mediated replication stress

Author

Kosar, Martin, Giannattasio, Michele, Piccini, Daniele, Maya-Mendoza, Apolinar, García-Benítez, Francisco, Bartkova, Jirina, Barroso, Sonia I., Gaillard, Hélène, Martini, Emanuele, Restuccia, Umberto, Ramirez-Otero, Miguel Angel, Garre, Massimiliano, Verga, Eleonora, Andújar-Sánchez, Miguel, Maynard, Scott, Hodny, Zdenek, Costanzo, Vincenzo, Kumar, Amit, Bachi, Angela, Aguilera, Andrés, Bartek, Jiri, and Foiani, Marco

Published
2021
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4. Lethal Influenza in Two Related Adults with Inherited GATA2 Deficiency

Author

Sologuren, Ithaisa, Martínez-Saavedra, María Teresa, Solé-Violán, Jordi, de Borges de Oliveira Jr, Edgar, Betancor, Eva, Casas, Inmaculada, Oleaga-Quintas, Carmen, Martínez-Gallo, Mónica, Zhang, Shen-Ying, Pestano, Jose, Colobran, Roger, Herrera-Ramos, Estefanía, Pérez, Carmen, López-Rodríguez, Marta, Ruiz-Hernández, José Juan, Franco, Nieves, Ferrer, José María, Bilbao, Cristina, Andújar-Sánchez, Miguel, Álvarez Fernández, Mercedes, Ciancanelli, Michael J., Rodríguez de Castro, Felipe, Casanova, Jean-Laurent, Bustamante, Jacinta, and Rodríguez-Gallego, Carlos

Published
2018
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7. Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps

Author

Paes Dias, Mariana, primary, Tripathi, Vivek, additional, van der Heijden, Ingrid, additional, Cong, Ke, additional, Manolika, Eleni-Maria, additional, Bhin, Jinhyuk, additional, Gogola, Ewa, additional, Galanos, Panagiotis, additional, Annunziato, Stefano, additional, Lieftink, Cor, additional, Andújar-Sánchez, Miguel, additional, Chakrabarty, Sanjiban, additional, Smith, Graeme C.M., additional, van de Ven, Marieke, additional, Beijersbergen, Roderick L., additional, Bartkova, Jirina, additional, Rottenberg, Sven, additional, Cantor, Sharon, additional, Bartek, Jiri, additional, Ray Chaudhuri, Arnab, additional, and Jonkers, Jos, additional

Published
2021
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8. The human nucleoporin Tpr protects cells from RNA-mediated replication stress

Author

Universidad de Sevilla. Departamento de Genética, Kosar, Martin, Giannattasio, Michele, Piccini, Daniele, Maya Mendoza, Apolinar, García Benítez, Francisco, Bartkova, Jirina, Barroso Ceballos, Sonia Inés, Gaillard, Hélène, Martini, Emanuele, Restuccia, Umberto, Ramírez Otero, Miguel Ángel, Garre, Massimiliano, Verga, Eleonora, Andújar Sánchez, Miguel, Maynard, Scott, Hodny, Zdenek, Costanzo, Vincenzo, Kumar, Amit, Bachi, Angela, Aguilera López, Andrés, Bartek, Jiri, Foiani, Marco, Universidad de Sevilla. Departamento de Genética, Kosar, Martin, Giannattasio, Michele, Piccini, Daniele, Maya Mendoza, Apolinar, García Benítez, Francisco, Bartkova, Jirina, Barroso Ceballos, Sonia Inés, Gaillard, Hélène, Martini, Emanuele, Restuccia, Umberto, Ramírez Otero, Miguel Ángel, Garre, Massimiliano, Verga, Eleonora, Andújar Sánchez, Miguel, Maynard, Scott, Hodny, Zdenek, Costanzo, Vincenzo, Kumar, Amit, Bachi, Angela, Aguilera López, Andrés, Bartek, Jiri, and Foiani, Marco

Abstract

Although human nucleoporin Tpr is frequently deregulated in cancer, its roles are poorly understood. Here we show that Tpr depletion generates transcription-dependent replication stress, DNA breaks, and genomic instability. DNA fiber assays and electron microscopy visualization of replication intermediates show that Tpr deficient cells exhibit slow and asymmetric replication forks under replication stress. Tpr deficiency evokes enhanced levels of DNA-RNA hybrids. Additionally, complementary proteomic strategies identify a network of Tpr-interacting proteins mediating RNA processing, such as MATR3 and SUGP2, and functional experiments confirm that their depletion trigger cellular phenotypes shared with Tpr deficiency. Mechanistic studies reveal the interplay of Tpr with GANP, a component of the TREX-2 complex. The Tpr-GANP interaction is supported by their shared protein level alterations in a cohort of ovarian carcinomas. Our results reveal links between nucleoporins, DNA transcription and replication, and the existence of a network physically connecting replication forks with transcription, splicing, and mRNA export machinery.

Published
2021

9. The human nucleoporin Tpr protects cells from RNA-mediated replication stress

Author

Associazione Italiana per la Ricerca sul Cancro, Danish Cancer Society Research Center, Danish National Research Foundation, Swedish Research Council, Lundbeck Foundation, Technology Agency of the Czech Republic, European Research Council, Ministerio de Economía y Competitividad (España), European Commission, Ministerio de Educación, Cultura y Deporte (España), Fondazione Umberto Veronesi, Kosar, Martin, Giannattasio, Michele, Piccini, Daniele, Maya-Mendoza, Apolinar, García-Benítez, Francisco, Bartkova, Jirina, Barroso, Sonia, Gaillard, Hélène, Martini, Emanuele, Restuccia, Umberto, Ramírez-Otero, Miguel Ángel, Garre, Massimiliano, Verga, Eleonora, Andújar-Sánchez, Miguel, Maynard, Scott, Hodny, Zdenek, Costanzo, Vicenzo, Kumar, Amit, Bachi, Angela, Aguilera, Andrés, Bartek, Jiri, Foiani, Marco, Associazione Italiana per la Ricerca sul Cancro, Danish Cancer Society Research Center, Danish National Research Foundation, Swedish Research Council, Lundbeck Foundation, Technology Agency of the Czech Republic, European Research Council, Ministerio de Economía y Competitividad (España), European Commission, Ministerio de Educación, Cultura y Deporte (España), Fondazione Umberto Veronesi, Kosar, Martin, Giannattasio, Michele, Piccini, Daniele, Maya-Mendoza, Apolinar, García-Benítez, Francisco, Bartkova, Jirina, Barroso, Sonia, Gaillard, Hélène, Martini, Emanuele, Restuccia, Umberto, Ramírez-Otero, Miguel Ángel, Garre, Massimiliano, Verga, Eleonora, Andújar-Sánchez, Miguel, Maynard, Scott, Hodny, Zdenek, Costanzo, Vicenzo, Kumar, Amit, Bachi, Angela, Aguilera, Andrés, Bartek, Jiri, and Foiani, Marco

Abstract

Although human nucleoporin Tpr is frequently deregulated in cancer, its roles are poorly understood. Here we show that Tpr depletion generates transcription-dependent replication stress, DNA breaks, and genomic instability. DNA fiber assays and electron microscopy visualization of replication intermediates show that Tpr deficient cells exhibit slow and asymmetric replication forks under replication stress. Tpr deficiency evokes enhanced levels of DNA-RNA hybrids. Additionally, complementary proteomic strategies identify a network of Tpr-interacting proteins mediating RNA processing, such as MATR3 and SUGP2, and functional experiments confirm that their depletion trigger cellular phenotypes shared with Tpr deficiency. Mechanistic studies reveal the interplay of Tpr with GANP, a component of the TREX-2 complex. The Tpr-GANP interaction is supported by their shared protein level alterations in a cohort of ovarian carcinomas. Our results reveal links between nucleoporins, DNA transcription and replication, and the existence of a network physically connecting replication forks with transcription, splicing, and mRNA export machinery.

Published
2021

10. Loss of Nuclear DNA Ligase III Reverts PARP Inhibitor Resistance in BRCA1/53BP1 Double-deficient Cells by Exposing ssDNA Gaps

Author

Dias, Mariana Paes, primary, Tripathi, Vivek, additional, van der Heijden, Ingrid, additional, Cong, Ke, additional, Manolika, Eleni-Maria, additional, Bhin, Jinhyuk, additional, Gogola, Ewa, additional, Galanos, Panagiotis, additional, Annunziato, Stefano, additional, Lieftink, Cor, additional, Andújar-Sánchez, Miguel, additional, Chakrabarty, Sanjiban, additional, Smith, Graeme C. M., additional, van de Ven, Marieke, additional, Beijersbergen, Roderick L., additional, Bartkova, Jirina, additional, Rottenberg, Sven, additional, Cantor, Sharon, additional, Bartek, Jiri, additional, Chaudhuri, Arnab Ray, additional, and Jonkers, Jos, additional

Published
2021
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12. Loss of Nuclear DNA Ligase III Reverts PARP Inhibitor Resistance in BRCA1-Deficient Cells by Increasing DNA Replication Stress

Author

Paes Dias, Mariana, primary, Tripathi, Vivek, additional, van der Heijden, Ingrid, additional, Cong, Ke, additional, Manolika, Eleni-Maria, additional, Galanos, Panagiotis, additional, Gogola, Ewa, additional, Annunziato, Stefano, additional, Lieftink, Cor, additional, Andújar-Sánchez, Miguel, additional, van de Ven, Marieke, additional, Chakrabarty, Sanjiban, additional, Beijersbergen, Roderick L., additional, Bartkova, Jirina, additional, Rottenberg, Sven, additional, Cantor, Sharon, additional, Bartek, Jiri, additional, Chaudhuri, Arnab Ray, additional, and Jonkers, Jos, additional

Published
2020
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14. Correction: Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality

Author

Gogola, Ewa, Duarte, Alexandra A, de Ruiter, Julian R, Wiegant, Wouter W, Schmid, Jonas A, de Bruijn, Roebi, James, Dominic I, Llobet, Sergi Guerrero, Vis, Daniel J, Annunziato, Stefano, van den Broek, Bram, Barazas, Marco, Kersbergen, Ariena, van de Ven, Marieke, Tarsounas, Madalena, Ogilvie, Donald J, van Vugt, Marcel, Wessels, Lodewyk F A, Bartkova, Jirina, Gromova, Irina, Andújar-Sánchez, Miguel, Bartek, Jiri, Lopes, Massimo, van Attikum, Haico, Borst, Piet, Jonkers, Jos, Rottenberg, Sven, and University of Zurich

Subjects
1307 Cell Biology, 10061 Institute of Molecular Cancer Research, 570 Life sciences, biology, 610 Medicine & health, 2730 Oncology, 1306 Cancer Research
Published
2019

15. Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality

Author

Gogola, Ewa, primary, Duarte, Alexandra A., additional, de Ruiter, Julian R., additional, Wiegant, Wouter W., additional, Schmid, Jonas A., additional, de Bruijn, Roebi, additional, James, Dominic I., additional, Llobet, Sergi Guerrero, additional, Vis, Daniel J., additional, Annunziato, Stefano, additional, van den Broek, Bram, additional, Barazas, Marco, additional, Kersbergen, Ariena, additional, van de Ven, Marieke, additional, Tarsounas, Madalena, additional, Ogilvie, Donald J., additional, van Vugt, Marcel, additional, Wessels, Lodewyk F.A., additional, Bartkova, Jirina, additional, Gromova, Irina, additional, Andújar-Sánchez, Miguel, additional, Bartek, Jiri, additional, Lopes, Massimo, additional, van Attikum, Haico, additional, Borst, Piet, additional, Jonkers, Jos, additional, and Rottenberg, Sven, additional

Published
2019
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16. Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality

Author

Gogola, Ewa, primary, Duarte, Alexandra A., additional, de Ruiter, Julian R., additional, Wiegant, Wouter W., additional, Schmid, Jonas A., additional, de Bruijn, Roebi, additional, James, Dominic I., additional, Guerrero Llobet, Sergi, additional, Vis, Daniel J., additional, Annunziato, Stefano, additional, van den Broek, Bram, additional, Barazas, Marco, additional, Kersbergen, Ariena, additional, van de Ven, Marieke, additional, Tarsounas, Madalena, additional, Ogilvie, Donald J., additional, van Vugt, Marcel, additional, Wessels, Lodewyk F.A., additional, Bartkova, Jirina, additional, Gromova, Irina, additional, Andújar-Sánchez, Miguel, additional, Bartek, Jiri, additional, Lopes, Massimo, additional, van Attikum, Haico, additional, Borst, Piet, additional, Jonkers, Jos, additional, and Rottenberg, Sven, additional

Published
2018
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17. TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity

Author

Moudry, Pavel, Watanabe, Kenji, Wolanin, Kamila M., Bartkova, Jirina, Wassing, Isabel E., Watanabe, Sugiko, Strauss, Robert, Pedersen, Rune Troelsgaard, Østergaard, Vibe Hallundbæk, Lisby, Michael, Andújar-Sánchez, Miguel, Maya-Mendoza, Apolinar, Esashi, Fumiko, Lukas, Jiri, Bartek, Jiri, Moudry, Pavel, Watanabe, Kenji, Wolanin, Kamila M., Bartkova, Jirina, Wassing, Isabel E., Watanabe, Sugiko, Strauss, Robert, Pedersen, Rune Troelsgaard, Østergaard, Vibe Hallundbæk, Lisby, Michael, Andújar-Sánchez, Miguel, Maya-Mendoza, Apolinar, Esashi, Fumiko, Lukas, Jiri, and Bartek, Jiri

Abstract

Topoisomerase IIβ-binding protein 1 (TOPBP1) participates in DNA replication and DNA damage response; however, its role in DNA repair and relevance for human cancer remain unclear. Here, through an unbiased small interfering RNA screen, we identified and validated TOPBP1 as a novel determinant whose loss sensitized human cells to olaparib, an inhibitor of poly(ADP-ribose) polymerase. We show that TOPBP1 acts in homologous recombination (HR) repair, impacts olaparib response, and exhibits aberrant patterns in subsets of human ovarian carcinomas. TOPBP1 depletion abrogated RAD51 loading to chromatin and formation of RAD51 foci, but without affecting the upstream HR steps of DNA end resection and RPA loading. Furthermore, TOPBP1 BRCT domains 7/8 are essential for RAD51 foci formation. Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin. Overall, our results provide mechanistic insights into TOPBP1's role in HR, with potential clinical implications for cancer treatment.

Published
2016

18. TOPBP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity

Author

Moudry, Pavel, primary, Watanabe, Kenji, additional, Wolanin, Kamila M., additional, Bartkova, Jirina, additional, Wassing, Isabel E., additional, Watanabe, Sugiko, additional, Strauss, Robert, additional, Troelsgaard Pedersen, Rune, additional, Oestergaard, Vibe H., additional, Lisby, Michael, additional, Andújar-Sánchez, Miguel, additional, Maya-Mendoza, Apolinar, additional, Esashi, Fumiko, additional, Lukas, Jiri, additional, and Bartek, Jiri, additional

Published
2016
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19. Nefroma mesoblástico congénito

Author

Arias Santos, María Dolores, primary, Pavcovich Ruiz, Marta, additional, Andújar Sánchez, Miguel, additional, Martínez Lanao, David, additional, and León Arencibia, Laureano, additional

Published
2006
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21. Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality

Author

Gogola, Ewa, Duarte, Alexandra A, De Ruiter, Julian R, Wiegant, Wouter W, Schmid, Jonas A, De Bruijn, Roebi, James, Dominic I, Guerrero Llobet, Sergi, Vis, Daniel J, Annunziato, Stefano, Van Den Broek, Bram, Barazas, Marco, Kersbergen, Ariena, Van De Ven, Marieke, Tarsounas, Madalena, Ogilvie, Donald J, Van Vugt, Marcel, Wessels, Lodewyk F A, Bartkova, Jirina, Gromova, Irina, Andújar-Sánchez, Miguel, Bartek, Jiri, Lopes, Massimo, Van Attikum, Haico, Borst, Piet, Jonkers, Jos, and Rottenberg, Sven

Subjects
630 Agriculture, 570 Life sciences, biology, 610 Medicine & health, 3. Good health
Abstract

Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically.

22. TOP BP1 regulates RAD51 phosphorylation and chromatin loading and determines PARP inhibitor sensitivity.

Author

Moudry, Pavel, Kenji Watanabe, Wolanin, Kamila M., Bartkova, Jirina, Wassing, Isabel E., Sugiko Watanabe, Strauss, Robert, Pedersen, Rune Troelsgaard, Oestergaard, Vibe H., Lisby, Michael, Andújar-Sánchez, Miguel, Maya-Mendoza, Apolinar, Fumiko Esashi, Lukas, Jiri, and Bartek, Jiri

Subjects
*DNA topoisomerase II, *CHROMATIN, *POLY(ADP-ribose) polymerase, *PHOSPHORYLATION, *DNA replication, *DNA damage, *SMALL interfering RNA, *HOMOLOGOUS chromosomes
Abstract

Topoisomerase IIβ-binding protein 1 (TOP BP1) participates in DNA replication and DNA damage response; however, its role in DNA repair and relevance for human cancer remain unclear. Here, through an unbiased small interfering RNA screen, we identified and validated TOP BP1 as a novel determinant whose loss sensitized human cells to olaparib, an inhibitor of poly(ADP-ribose) polymerase. We show that TOP BP1 acts in homologous recombination (HR) repair, impacts olaparib response, and exhibits aberrant patterns in subsets of human ovarian carcinomas. TOP BP1 depletion abrogated RAD51 loading to chromatin and formation of RAD51 foci, but without affecting the upstream HR steps of DNA end resection and RPA loading. Furthermore, TOP BP1 BRCT domains 7/8 are essential for RAD51 foci formation. Mechanistically, TOP BP1 physically binds PLK1 and promotes PLK1 kinase--mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin. Overall, our results provide mechanistic insights into TOP BP1's role in HR, with potential clinical implications for cancer treatment. [ABSTRACT FROM AUTHOR]

Published
2016
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23. Cribado del cáncer de cérvix en Canarias: estudio poblacional

Author

Vega Guedes, Begoña, Andújar Sánchez, Miguel, García Hernández, José Angel, Trujillo Carrillo, José Luis, Facultad de Ciencias de La Salud, and Departamento de Ciencias Médicas y Quirúrgicas

Subjects
320108 Ginecología, 32 Ciencias médicas
Abstract

Programa de doctorado: Patología Quirúrgica, Reproducción Humana y Factores Psicológicos y el Proceso de Enfermar, [ES]Los estudios de prevalencia del virus del papiloma humano (VPH) son necesarios para la prevención del cáncer de cérvix dado que nos dan información sobre la utilidad del cribado con test VPH y nos permiten predecir el impacto de la vacunación profiláctica. Además, conocer los factores de riesgo relacionados con la infección es importante para identificar subgrupos de población que están en mayor riesgo de cáncer de cérvix y así poder adoptar estrategias de prevención.

Published
2016

24. CARCINOMA INVASOR DE CERVIX EN LAS PALMAS. TIPIFICACIÓN DEL VIRUS DEL PAPILOMA HUMANO (VPH) Y FACTORES PRONOSTICOS

Author

Arencibia Sánchez, Octavio, Andújar Sánchez, Miguel, Lubrano Rosales, Amina, and Departamento de Ciencias Médicas y Quirúrgicas

Subjects
320108 Ginecología
Abstract

Programa de doctorado: Patología Quirúrgica, Reproducción humana y factores psicológicos y el proceso de enfermar, [ES]Estudio retrospectivo destinado a estudiar los carcinomas infiltrantes de cérvix (estadio FIGO IB y superiores) registrados en la Unidad de Ginecología Oncológica del Complejo Hospitalario Universitario Materno Infantil entre los años 1996 y 2013. El tamaño muestral final fue de 561 pacientes, de las que se contaba con material disponible para el genotipado viral, lo que supone el 82% de las pacientes controladas en este periodo.

Published
2015
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25. Prevalencia de la infección genital por el virus del papiloma humano en la población femenina de Gran Canaria

Author

Torres Afonso, María Alejandra, Andújar Sánchez, Miguel, Lubrano Rosales, Amina, Facultad de Ciencias de la Salud, and Departamento de Ciencias Médicas y Quirúrgicas

Subjects
320106 Dermatología, 320108 Ginecología
Abstract

Programa de doctorado: Patología quirúrgica, reproducción humana y factores psicológicos y el proceso de enfermar En Canarias la tasa de mortalidad por cáncer de cuello de útero es superior a la nacional. Su agente etiológico es el virus del papiloma humano (VPH) y es de crucial importancia para el diseño y control de los programas de prevención primaria (vacunación) y secundaria (cribado) conocer la prevalencia de esta infección. El objetivo de este trabajo es determinar las prevalencias de las lesiones preneoplásticas del cérvix y de la infección por el VPH. Comprobar si difieren entre poblaciones seleccionadas al azar y problación voluntaria. Conocer los factores de riesgo para la adquisición de la infección.

Published
2015

26. Oesophageal squamous cell carcinoma in a young adult with IL-12R beta 1 deficiency.

Author

Cárdenes M, Angel-Moreno A, Fieschi C, Sologuren I, Colino E, Molinés A, García-Laorden MI, Campos-Herrero MI, Andújar-Sánchez M, Casanova JL, and Rodríguez-Gallego C

Subjects
Adolescent, Adult, Carcinoma, Squamous Cell pathology, Child, Esophageal Neoplasms pathology, Fatal Outcome, Female, Humans, Male, Receptors, Interleukin-12 metabolism, Young Adult, Carcinoma, Squamous Cell metabolism, Esophageal Neoplasms metabolism, Receptors, Interleukin-12 deficiency
Abstract

Genetic defects in the IL-12-IL-23/IFN-gamma circuit confer Mendelian susceptibility to mycobacteria and salmonella. The IL-12/IFN-gamma axis is essential for anti-tumoral immunity in mice. Cancer susceptibility has not been recognised in these patients so far. We report three relatives with IL-12R beta 1 deficiency. At the age of 25 years old, one patient presented with oesophageal squamous cell carcinoma (OSCC). The patient had no previous risk factors for OSCC. He died at the age of 29 years. OSCC is exceedingly rare in individuals under 30 years and frequently relates to alcohol intake and smoking. Disorders of the IL-12-IL-23/IFN-gamma axis may predispose to cancer.

Published
2010
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