The role of the Tousled Like Kinases in genome stability and mammalian development

Tesi vinculada a l'Institut de Recerca Biomèdica de Barcelona (IRBB)

Bibliographic Details
Author: González Burón, Helena
Format: doctoral thesis
Status:Published version
Publication Date:2014
Country:España
Institution:CBUC, CESCA
Repository:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/134985
Online Access:http://hdl.handle.net/10803/134985
Access Level:Open access
Keyword:Càncer
Cáncer
Cancer
Cultiu cel·lular
Cultivo celular
Cell culture
Cromatina
Chromatin
Reparació de l'ADN
Reparación del ácido desoxirribonucleico
DNA repair
Proteïnes quinases
Proteínas quinasas
Protein kinases
Ciències de la Salut
616
id ES_d4fbbce59d4736d909529de1900dd2cc
oai_identifier_str oai:www.tdx.cat:10803/134985
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv The role of the Tousled Like Kinases in genome stability and mammalian development
title The role of the Tousled Like Kinases in genome stability and mammalian development
spellingShingle The role of the Tousled Like Kinases in genome stability and mammalian development
González Burón, Helena
Càncer
Cáncer
Cancer
Cultiu cel·lular
Cultivo celular
Cell culture
Cromatina
Chromatin
Reparació de l'ADN
Reparación del ácido desoxirribonucleico
DNA repair
Proteïnes quinases
Proteínas quinasas
Protein kinases
Ciències de la Salut
616
title_short The role of the Tousled Like Kinases in genome stability and mammalian development
title_full The role of the Tousled Like Kinases in genome stability and mammalian development
title_fullStr The role of the Tousled Like Kinases in genome stability and mammalian development
title_full_unstemmed The role of the Tousled Like Kinases in genome stability and mammalian development
title_sort The role of the Tousled Like Kinases in genome stability and mammalian development
dc.creator.none.fl_str_mv González Burón, Helena
author González Burón, Helena
author_facet González Burón, Helena
author_role author
dc.contributor.none.fl_str_mv Stracker, Travis
Universitat de Barcelona. Facultat de Farmàcia
dc.subject.none.fl_str_mv Càncer
Cáncer
Cancer
Cultiu cel·lular
Cultivo celular
Cell culture
Cromatina
Chromatin
Reparació de l'ADN
Reparación del ácido desoxirribonucleico
DNA repair
Proteïnes quinases
Proteínas quinasas
Protein kinases
Ciències de la Salut
616
topic Càncer
Cáncer
Cancer
Cultiu cel·lular
Cultivo celular
Cell culture
Cromatina
Chromatin
Reparació de l'ADN
Reparación del ácido desoxirribonucleico
DNA repair
Proteïnes quinases
Proteínas quinasas
Protein kinases
Ciències de la Salut
616
description Tesi vinculada a l'Institut de Recerca Biomèdica de Barcelona (IRBB)
publishDate 2014
dc.date.none.fl_str_mv 2014
2014
2016
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/134985
url http://hdl.handle.net/10803/134985
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 184 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869420594025463809
spelling The role of the Tousled Like Kinases in genome stability and mammalian developmentGonzález Burón, HelenaCàncerCáncerCancerCultiu cel·lularCultivo celularCell cultureCromatinaChromatinReparació de l'ADNReparación del ácido desoxirribonucleicoDNA repairProteïnes quinasesProteínas quinasasProtein kinasesCiències de la Salut616Tesi vinculada a l'Institut de Recerca Biomèdica de Barcelona (IRBB)The human Tousled-like kinases 1 and 2 (TLKs) are predicted serine/threonine kinases that show maximal activity in S phase and are transiently inhibited by the DNA damage response (DDR). Both TLKs interact with and phosphorylate each other and the histone chaperone Asf1. Asf1 plays a critical role in regulating histone pools during several cellular processes, suggesting that the primary function of TLKs could be in the regulation of chromatin assembly during transcription, replication and repair processes. Thus, we hypothesize that reduction of TLK activity will impact on the function of Asf1, and perhaps other chromatin modulators, affecting key cellular processes that maintain genome integrity and proliferative capacity. In order to examine the in vivo consequences of TLK1 or TLK2 loss of function, we generated mice harboring genetraps that inhibit the expression of either gene. Surprisingly, mice lacking TLK1 were born normally, showed no overt pathology and aged normally over 18 months. Examination of developmental processes, such as lymphocyte maturation, revealed no abnormalities, and the DNA replication and cell cycle progression were normal, even following DNA damage. To determine if TLK2 provided redundant functions, we performed transient siRNA depletion of TLK2 in wild type and TLK1 null cell cultures. While this led to no defects in survival in WT cells, TLK1 mutants were profoundly sensitized to DNA damaging agents. We next generated mice harboring a genetrap allele to block the expression of TLK2. In contrast to TLK1, no liveborn homozygous mutants have been observed and embryos isolated for MEFs are severely runted, displaying heterogeneous defects including failure to close the neural tube and placental impairment. These data indicated that TLK1 and TLK2 do not play equivalent roles during development. Given that we see an acute response to DNA damage under conditions where total TLK activity is reduced and it is unlikely that cells lacking all TLK activity can support proliferation, we believe that the modulation of TLK activity represents a potentially valuable therapeutic approach. Collectively, the work I have presented represents a significant advance in our understanding of TLK function in cells and in mammalian development and supports the possibility that TLKs represent a potentially valuable target for the treatment of human disease.Universitat de BarcelonaStracker, TravisUniversitat de Barcelona. Facultat de Farmàcia201420162014info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion184 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/134985TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/1349852026-06-14T12:46:07Z
score 15,301603

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