Novel Regulators of Telomerase-Independent Telomere Elongation in ALT Cancer Cells
Autor(a) principal: | |
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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 |
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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 |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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