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Interactome of Ixr1, HMGB1 and HMGB2 Proteins in Relation to Their Cellular Functions

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Interactome of Ixr1, HMGB1 and HMGB2 proteins in relation to their cellular functions Aida Inés Barreiro Alonso PhD Thesis 2017 Directors: Dra. Mª Esperanza Cerdán Villanueva and Dra. Mónica Lamas Maceiras Programa Oficial de Doutoramento en Bioloxía Celular e Molecular El presente trabajo, Interactome of Ixr1, HMGB1 and HMGB2 proteins in relation to their cellular functions, presentado por Doña Aida Inés Barreiro Alonso para aspirar al grado de doctor en Bioquímica, ha sido realizado bajo nuestra dirección en el Departamento de Biología, de la Universidad de A Coruña. Revisado el texto. Estamos conformes con su presentación para ser juzgado. A Coruña, 9 de noviembre de 2017 VºBº VºBº Dra. Mº Esperanza Cerdán Dra. Mónica Lamas Maceiras Villanueva Catedrática de Bioquímica y Profesora de Bioquímica y Biología Molecular Biología Molecular La autora de este trabajo ha disfrutado durante la realización de esta tesis de un contrato a cargo de proyecto por la Universidade da Coruña (julio de 2013‐noviembre de 2013), un contrato predoctoral asociado al plan I2C de la Xunta de Galicia para el año 2013 (1 diciembre 2013‐30 noviembre 2016). Parte del trabajo se realizó en el “Wellcome Trust Sanger Institute” (Hinxton, United Kingdom) entre septiembre de 2016 y Marzo de 2017 en el grupo “Proteomic Mass Spectrometry”. Esta estancia fue financiada por el programa de ayudas predoctorales para estancias Inditex‐UDC y por las ayudas para estancias pre y posdoctorales de investigación para personal de grupos de la agrupación estratégica CICA‐INIBIC. La realización de este trabajo ha sido posible gracias a la financiación obtenida de los proyectos del Instituto de Salud Carlos III con referencia PI14/01031 y de la Xunta de Galicia (Consolidación Grupos referencia Competitiva Contractos no. CN2012‐118 y ED431C 2016‐012), ambos cofinanciados por FEDER. El trabajo realizado durante la estancia de investigación en el Wellcome Trust Sanger Institute fue financiado por el Wellcome Trust (grant number WT098051). A mis padres “I’m not a genius but I’m a terrific package of experience” (Chinese Fortune cookie, Sanger Institute, Cambridge 2017) En primer lugar me gustaría dar las gracias a Mª Esperanza Cerdán Villanueva y Mónica Lamas Maceiras, mis dos directoras de Tesis sin las cuales hoy no estaría aquí. Gracias por darme la oportunidad de aprender lo que de verdad significa “investigar” y de haberme dado la oportunidad no sólo de llevar a cabo mi Tesis doctoral si no de conocer a gente increíble que ya forman parte de mi vida. Como no, agradecer también a todos los profesores del laboratorio de Bioquímica de la UDC, Mª Isabel González Siso, Esther Rodríguez Belmonte, Manuel Becerra Fernández, Marian Freire Picos y Ana Rodríguez Torres la ayuda que me han prestado estos años. Y ahora viene lo difícil, a mí siempre me ha gustado leer las dedicatorias de las tesis y en el laboratorio de bioquímica ya me habéis hecho caer la lagrimilla más de una vez, pero ya os adelanté que a mí esto no se me da tan bien…En primer lugar quiero daros un GRACIAS enorme a todos los que habéis formado parte del laboratorio de Bioquímica durante los años en los que he hecho la tesis, porque gracias a vosotros he disfrutado de esta etapa. Cuando un experimento no sale y no tienes ni idea de por qué no ha salido, lo mejor que te puede pasar es tener a amigos que además de apoyarte en todo momento te dan soluciones y fuerzas para seguir. Porque me acuerdo cuando seguía a Ángel nada más entrar en el laboratorio y curioseaba lo que hacía. Gracias Ángel por ser un super‐predecesor, por contestar mails, whattsapps y skypes, y ayudarme desde donde estés, porque eres un crack y aunque no te guste que te lo diga…”Eres mi Rafa”. Mi Mariu, mi Mari, y mi Olalla, las tres chicas del laboratorio de bioquímica del 2013, tendría mil cosas que deciros, he pasado muchísimos momentos con vosotras en el laboratorio pero los más importantes son los que he pasado fuera, porque hemos pasado bodas, un bebé (y otro que llegará pronto), clases descoordinadas de aerolatinos y spinning, paseos con helados, momentos de risas y momentos no tan alegres pero que te unen un montón. Agustín, te admiro, admiro como has sido capaz de mantener la calma durante tu tesis y como consigues tranquilizarme y razonar conmigo, gracias por ayudarme todo este tiempo. Marta, nuestra “adoptada” del INIBIC, nos tienes que visitar más porque nos tienes muy abandonados con lo que nos gusta que vengas… Desde hace un tiempo se nos unió nuestra última adquisición, Maria “peque”, el labo ya no sería el mismo sin tus aventuras‐desventuras y mil anécdotas. No me olvido de Ana, mi primera TFG, y mucho más que eso, me has demostrado que siempre hay que mirar adelante y seguir con fuerza. Y aunque ya te he mencionado antes Mónica, te vuelvo a incluir aquí, entre los del “Labo”, porque sin ti el labo no sería lo que es. Y por supuesto Juanjo, mi vecino incondicional de escritorio y de poyata y sobre todo un gran amigo, un enorme gracias por aguantarme y tener una santa paciencia conmigo todos estos años. Hay muchas personas que habéis formado parte de este etapa en el laboratorio de Bioquímica a los que también me gustaría daros las gracias como a Rosa, Kamila, Blanca, Martín, Maya, Kike, Isabel…y muchos más que seguramente me estoy dejando en el tintero. Me gustaría también agradecerle a la Dra. Ángela Figueroa la oportunidad de aprender nuevas técnicas durante los meses que me acogieron en su grupo del INIBIC. Y por supuesto este aprendizaje no habría sido posible sin la ayuda de Raquel, Olalla, Isa, Andrea y mucha más gente del INIBIC que me ayudaron durante el tiempo que estuve allí, ¡gracias por acogerme en el grupo! Durante la realización de la tesis llevé a cabo una estancia de 6 meses en el Mass Spectrometry group (Team 17) en el Wellcome Trust Sanger Institute, tengo que dar un enorme gracias a la Dra. Mercedes Pardo, porque sin ella esta estancia no habría sido posible, por hacer que me sintiese totalmente integrada en el grupo y por toda la ayuda que me dio, gracias por ayudarme esos meses y seguir ayudándonos ahora. Como la mayor parte de las personas del grupo no hablan español voy a cambiar de idioma… I would like to thank Dr. Jyoti Choudhary, Team 17 leader, for accepting me in her group and giving me support as if I was one of her team´s member, thank you for believing in my work and for all the help. I learn a lot during my stay in the Team 17, but It was not just lab work, my months in Cambrdige were an amazing experience during which I met amazing people: Junting, Charly, George, Sharna…It wouldn´t have been the same without you! I would also want to thank the other Team 17 members Chris, Lu, Theo, Hendrik and Olallo. Hay una persona que aunque no es de ninguno de los laboratorios en los que he estado ha tenido un papel importante durante todo este tiempo, Santi (mi Ferro). Durante la tesis no todos son momentos buenos, también hay enfados, frustración y desánimos, que son los más difíciles, gracias por estar conmigo en todos esos momentos y apoyarme todo este tiempo. Probablemente el gracias más grande que tengo que dar es a mis padres, porque si es cierto que Esperanza y Mónica me dieron la oportunidad de llevar a cabo mi tesis en este laboratorio, no habría llegado a este punto sin ellos, sin su apoyo. Gracias por permitirme estudiar lo que he querido y por el apoyo, no sólo durante la carrera si no en todo lo que he hecho después porque sin vosotros no estaría donde estoy hoy. ¡Muchas gracias! Como no puedo mencionar a todo el mundo que me gustaría en estos agradecimientos, voy a dar un GRACIAS general a todos aquellos que formáis parte de mi vida y que me habéis apoyado durante este tiempo. Contents Short Abstracts 19 Introduction 25 Objectives 33 Chapter 1 37 The HMGB protein Ixr1 interacts with other proteins involved in transcriptional regulation Chapter 2 71 Delineating the HMGB1 and HMGB2 interactome in prostate and ovary epithelial cells and its relationship with cancer Chapter 3 117 Novel HMGB1 and HMGB2 interacting partners in prostate and ovarian tumoral cells Chapter 4 161 Nuclear and cytoplasmic interactions of HMGB1 in prostate and ovarian tumoral cells identified by an Immunoprecipitation/MS approach Chapter 5 245 A proteomic approach to the role of HMGB1 in the response of PC‐3 and SKOV‐3 cells to cisplatin Concluding remarks 263 Appendix ‐ Resumen 269 Short Abstracts Short Abstracts ABSTRACT The Saccharomyces cerevisiae protein, Ixr1, and human HMGB1 and HMGB2 proteins belong to the HMGB protein family. The main objective of this work was to identify new proteins binding Ixr1, HMGB1 and HMGB2 in order to increase the knowledge about their cellular functions. In yeast Ixr1 has activator or repressor activity on transcription in different promoters and controls the hypoxic response. The transcriptional activator domain of Ixr1 has been identified in its NH2 term in this study. Interactome studies show that Ixr1 binds to Ssn8 and this interaction might mediate the repressor function of Ixr1 on several promoters. Other proteins identified share functions associated to glucose metabolism, stress, and ribosome biogenesis among others. Differential phosphorylation of Ixr1 was observed depending on oxygen availability. The HMGB1 and HMGB2 interactomes were studied using different techniques as yeast two‐hybrid assays and purification methods coupled with mass spectrometry.
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