Novel Regulators of Telomerase-Independent Telomere Elongation in ALT Cancer Cells

Detalhes bibliográficos
Autor(a) principal: Moleirinho, Beatriz Pedrosa
Data de Publicação: 2020
Tipo de documento: Dissertação
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/47971
Resumo: Tese de mestrado, Biologia Molecular e Genética, Universidade de Lisboa, Faculdade de Ciências, 2020
id RCAP_b5c69b4db8ad6029c28e4ec070998fe6
oai_identifier_str oai:repositorio.ul.pt:10451/47971
network_acronym_str RCAP
network_name_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository_id_str 7160
spelling Novel Regulators of Telomerase-Independent Telomere Elongation in ALT Cancer CellsALTPC4telómerosstress replicativoTeses de mestrado - 2020Departamento de Biologia VegetalTese de mestrado, Biologia Molecular e Genética, Universidade de Lisboa, Faculdade de Ciências, 2020Telomeres are nucleoprotein structures located at the end of linear eukaryotic chromosomes. Telomeres have two main cellular functions, to protect chromosome ends from unwanted DNA processing and to act as a biological clock. Telomeres shorten at each cell division due to the so-called end replication problem. This progressive shortening eventually triggers replicative senescence. Cancer cells avoid senescence by activating a mechanism that enables telomere elongation. Two different mechanism exist: re-activation of the enzyme telomerase or the Alternative Lengthening of Telomeres (ALT) pathway. ALT relies on homology-direct repair (HDR) of damaged telomeres, hence ALT telomeres need to be maintained physiologically unstable. This is achieved by endogenous replication stress accumulating at ALT telomeres. However, this DNA instability has to be kept below tolerance levels in order to avoid cell cycle arrest and death. Several factors have been identified as alleviators of telomeric replication stress in ALT cells, including the endoribonuclease RNaseH1 and the translocase FANCM. Positive co-factor 4 (PC4) is involved in different cellular functions, including transcription, DNA replication, maintenance of genome stability and chromatin organization. Moreover, PC4 is able to bind ssDNA, dsDNA, RNA and G-quadruplexes structures, and its localization on chromatin increases upon replication stress. This study aims at assessing if PC4 is an alleviator of ALT-specific telomeric replication stress (ATRS). I show, by indirect immunofluorescence, that PC4 localizes to telomeres and that its recruitment is enhanced when telomeric replication stress is induced through depletion of the telomeric factor TRF1. Moreover, PC4 recruitment to ALT telomeres increases upon depletion of FANCM and RNaseH1. Treatment with RNaseA shows that PC4 localization at ALT telomeres is at least in part mediated by RNA. Furthermore, expression of an ectopic PC4 mutant, W89A, shows that the capacity of PC4 to bind to ssDNA is not essential for telomere recruitment. I also show that PC4 supports ALT telomere stability since its depletion leads to accumulation of DNA damage markers at telomeres in ALT cells. This coincides with arrest of ALT cell proliferation and cell death. This work shows that PC4 is important for ALT cell viability, likely by alleviating telomeric replication stress and avoiding excessive telomere instability. Besides uncovering a novel regulator of replication stress at ALT telomeres and further refining our understanding of ALT, this work suggests that PC4 might become an interesting target for the development of therapeutic strategies against ALT tumors.Azzalin, Claus M.Zilhão, Rita, 1959-Repositório da Universidade de LisboaMoleirinho, Beatriz Pedrosa2023-12-27T01:32:41Z202020202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttp://hdl.handle.net/10451/47971TID:202599450enginfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-01-01T01:16:22Zoai:repositorio.ul.pt:10451/47971Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:59:55.208846Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Novel Regulators of Telomerase-Independent Telomere Elongation in ALT Cancer Cells
title Novel Regulators of Telomerase-Independent Telomere Elongation in ALT Cancer Cells
spellingShingle Novel Regulators of Telomerase-Independent Telomere Elongation in ALT Cancer Cells
Moleirinho, Beatriz Pedrosa
ALT
PC4
telómeros
stress replicativo
Teses de mestrado - 2020
Departamento de Biologia Vegetal
title_short Novel Regulators of Telomerase-Independent Telomere Elongation in ALT Cancer Cells
title_full Novel Regulators of Telomerase-Independent Telomere Elongation in ALT Cancer Cells
title_fullStr Novel Regulators of Telomerase-Independent Telomere Elongation in ALT Cancer Cells
title_full_unstemmed Novel Regulators of Telomerase-Independent Telomere Elongation in ALT Cancer Cells
title_sort Novel Regulators of Telomerase-Independent Telomere Elongation in ALT Cancer Cells
author Moleirinho, Beatriz Pedrosa
author_facet Moleirinho, Beatriz Pedrosa
author_role author
dc.contributor.none.fl_str_mv Azzalin, Claus M.
Zilhão, Rita, 1959-
Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Moleirinho, Beatriz Pedrosa
dc.subject.por.fl_str_mv ALT
PC4
telómeros
stress replicativo
Teses de mestrado - 2020
Departamento de Biologia Vegetal
topic ALT
PC4
telómeros
stress replicativo
Teses de mestrado - 2020
Departamento de Biologia Vegetal
description Tese de mestrado, Biologia Molecular e Genética, Universidade de Lisboa, Faculdade de Ciências, 2020
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020-01-01T00:00:00Z
2023-12-27T01:32:41Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/47971
TID:202599450
url http://hdl.handle.net/10451/47971
identifier_str_mv TID:202599450
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
_version_ 1799134545660870656

Registros relacionados