{"id":{"repo_id":"sevilla","oai_identifier":"oai:idus.us.es:11441/177460"},"canonical_url":"https://search.dev.ndltd.org/etd/sevilla/oai:idus.us.es:11441/177460","repository":{"repo_id":"sevilla","name":"Universidad de Sevilla","base_url":"https://idus.us.es/server/oai/request"},"display":{"title":"The circadian Control of DNA end Resection","abstract":"Even though double-strand breaks (DSBs) stand as the most cytotoxic lesion the cell can endure, they have evolved two major pathways to counter these: the religation of the broken ends (Non-Homologous End-Joining, NHEJ) and the repair of the lesion using a homologue sequence (Homology-Directed Repair, HDR). The choice between these two pathways is crucial for cell fitness and is controlled by an exquisite regulatory system. In this thesis, we uncovered a novel role for the circadian clock in the regulation of DNA end resection, the licensing step of HDR. Thus, we demonstrated that the circadian factor CRY1 drives circadian oscillations in DNA end resection, which results in circadian fluctuations in HDR. Mechanistically, we show how this protein is recruited to the DSB in a manner dependent on the apical kinase DNA-PK and favors the retention of the anti-resection factor CCAR2, which counteracts CtIP, the key factor permitting DNA end processing. Furthermore, not only do we describe how CRY1 expression levels impact genome stability and modulate cancer response to treatment, but also how time of the day impacts cancer response to radiation therapy as a reflection of this.","abstract_html":"Even though double-strand breaks (DSBs) stand as the most cytotoxic lesion the cell can endure, they have evolved two major pathways to counter these: the religation of the broken ends (Non-Homologous End-Joining, NHEJ) and the repair of the lesion using a homologue sequence (Homology-Directed Repair, HDR). The choice between these two pathways is crucial for cell fitness and is controlled by an exquisite regulatory system. In this thesis, we uncovered a novel role for the circadian clock in the regulation of DNA end resection, the licensing step of HDR. Thus, we demonstrated that the circadian factor CRY1 drives circadian oscillations in DNA end resection, which results in circadian fluctuations in HDR. Mechanistically, we show how this protein is recruited to the DSB in a manner dependent on the apical kinase DNA-PK and favors the retention of the anti-resection factor CCAR2, which counteracts CtIP, the key factor permitting DNA end processing. Furthermore, not only do we describe how CRY1 expression levels impact genome stability and modulate cancer response to treatment, but also how time of the day impacts cancer response to radiation therapy as a reflection of this.","abstract_has_math":false,"creators":["Romero Franco, Amador"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Huertas Sánchez, Pablo"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-06-27","date_published":"2025-06-27","updated_at":"2026-07-24T04:29:30Z","subjects":[],"languages":["eng"],"rights":["Attribution-NonCommercial-NoDerivatives 4.0 International"],"rights_urls":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/11441/177460","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Huertas Sánchez, Pablo"]},{"key":"dc:creator","label":"Author","values":["Romero Franco, Amador"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-10-06T07:47:04Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2025-10-06T07:47:04Z"]},{"key":"dc:date.issued","label":"Date","values":["2025-06-27"]},{"key":"dc:type","label":"Dc Type","values":["doctoral thesis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Attribution-NonCommercial-NoDerivatives 4.0 International"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://creativecommons.org/licenses/by-nc-nd/4.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/11441/177460"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Even though double-strand breaks (DSBs) stand as the most cytotoxic lesion the cell can endure, they have evolved two major pathways to counter these: the religation of the broken ends (Non-Homologous End-Joining, NHEJ) and the repair of the lesion using a homologue sequence (Homology-Directed Repair, HDR). The choice between these two pathways is crucial for cell fitness and is controlled by an exquisite regulatory system. In this thesis, we uncovered a novel role for the circadian clock in the regulation of DNA end resection, the licensing step of HDR. Thus, we demonstrated that the circadian factor CRY1 drives circadian oscillations in DNA end resection, which results in circadian fluctuations in HDR. Mechanistically, we show how this protein is recruited to the DSB in a manner dependent on the apical kinase DNA-PK and favors the retention of the anti-resection factor CCAR2, which counteracts CtIP, the key factor permitting DNA end processing. Furthermore, not only do we describe how CRY1 expression levels impact genome stability and modulate cancer response to treatment, but also how time of the day impacts cancer response to radiation therapy as a reflection of this.","A pesar de que los cortes de doble cadena (DSBs) son una de las lesiones más citotóxicas para las células, estas han desarrollado a lo largo de la evolución dos mecanismos mayoritarios para contrarrestarlos: la religación de los extremos del corte (Unión de extremos no homólogos, NHEJ) y la reparación de estas lesiones usando como molde una secuencia homóloga (Reparación dirigida por homología, HDR). La elección entre estas dos es una cuestión crucial para la supervivencia celular, y es por ello que está controlada por un sofisticado sistema regulatorio. En esta tesis hemos descubierto una nueva función del reloj circadiano en la regulación de la resección del ADN, proceso que actúa como prerrequisito indispensable para la HDR. Así, hemos demostrado como el miembro del reloj circadiano CRY1 protagoniza las oscilaciones circadianas en la resección del ADN, resultando en oscilaciones en la HDR. A nivel molecular, hemos demostrado como esta proteína se recluta al DSB gracias a la quinasa apical DNA-PK y favorece en este la retención del factor anti-resección CCAR2, quien contrarresta a CtIP, factor clave en la resección del ADN. Finalmente, también describimos cómo los niveles de expresión de CRY1 influyen en la estabilidad del genoma y modulan la respuesta al tratamiento del cáncer, y además mostramos cómo esto se refleja en una respuesta diferencial a la radioterapia en función de la hora del día."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["The circadian Control of DNA end Resection"]}]}],"canonical_facts":{"dc:contributor.advisor":["Huertas Sánchez, Pablo"],"dc:creator":["Romero Franco, Amador"],"dc:date.accessioned":["2025-10-06T07:47:04Z"],"dc:date.available":["2025-10-06T07:47:04Z"],"dc:date.issued":["2025-06-27"],"dc:description.abstract":["Even though double-strand breaks (DSBs) stand as the most cytotoxic lesion the cell can endure, they have evolved two major pathways to counter these: the religation of the broken ends (Non-Homologous End-Joining, NHEJ) and the repair of the lesion using a homologue sequence (Homology-Directed Repair, HDR). The choice between these two pathways is crucial for cell fitness and is controlled by an exquisite regulatory system. In this thesis, we uncovered a novel role for the circadian clock in the regulation of DNA end resection, the licensing step of HDR. Thus, we demonstrated that the circadian factor CRY1 drives circadian oscillations in DNA end resection, which results in circadian fluctuations in HDR. Mechanistically, we show how this protein is recruited to the DSB in a manner dependent on the apical kinase DNA-PK and favors the retention of the anti-resection factor CCAR2, which counteracts CtIP, the key factor permitting DNA end processing. Furthermore, not only do we describe how CRY1 expression levels impact genome stability and modulate cancer response to treatment, but also how time of the day impacts cancer response to radiation therapy as a reflection of this.","A pesar de que los cortes de doble cadena (DSBs) son una de las lesiones más citotóxicas para las células, estas han desarrollado a lo largo de la evolución dos mecanismos mayoritarios para contrarrestarlos: la religación de los extremos del corte (Unión de extremos no homólogos, NHEJ) y la reparación de estas lesiones usando como molde una secuencia homóloga (Reparación dirigida por homología, HDR). La elección entre estas dos es una cuestión crucial para la supervivencia celular, y es por ello que está controlada por un sofisticado sistema regulatorio. En esta tesis hemos descubierto una nueva función del reloj circadiano en la regulación de la resección del ADN, proceso que actúa como prerrequisito indispensable para la HDR. Así, hemos demostrado como el miembro del reloj circadiano CRY1 protagoniza las oscilaciones circadianas en la resección del ADN, resultando en oscilaciones en la HDR. A nivel molecular, hemos demostrado como esta proteína se recluta al DSB gracias a la quinasa apical DNA-PK y favorece en este la retención del factor anti-resección CCAR2, quien contrarresta a CtIP, factor clave en la resección del ADN. Finalmente, también describimos cómo los niveles de expresión de CRY1 influyen en la estabilidad del genoma y modulan la respuesta al tratamiento del cáncer, y además mostramos cómo esto se refleja en una respuesta diferencial a la radioterapia en función de la hora del día."],"dc:format":["application/pdf"],"dc:identifier.uri":["https://hdl.handle.net/11441/177460"],"dc:language.iso":["eng"],"dc:rights":["Attribution-NonCommercial-NoDerivatives 4.0 International"],"dc:rights.uri":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"dc:title":["The circadian Control of DNA end Resection"],"dc:type":["doctoral thesis"]},"updated_at":"2026-07-24T04:29:30Z"}