Dysfunctional telomeres in primary cells from Fanconi anemia FANCD2 patients

Background: Fanconi anemia (FA) is characterized by sensitivity to DNA cross-linking agents, mild cellular, and marked clinical radio sensitivity. In this study we investigated telomeric abnormalities of non-immortalized primary cells (lymphocytes and fibroblasts) derived from FA patients of the FA-...

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Autores: Joksic, Ivana, Vujic, Dragana, Guc-Scekic, Marija, Leskovac, Andreja, Petrovic, Sandra, Ojani, Maryam, Trujillo Quintero, Juan Pablo, Surralles, Jordi|||0000-0002-4041-7519, Zivkovic, Maja, Stankovic, Aleksandra, Slijepcevic, Pedrag, Joksic, Gordana
Tipo de recurso: artículo
Fecha de publicación:2012
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:113422
Acceso en línea:https://ddd.uab.cat/record/113422
https://dx.doi.org/urn:doi:10.1186/2041-9414-3-6
Access Level:acceso abierto
Palabra clave:Primary FA cells
Telomere dysfunction
Expression of TRF1 and TRF2
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spelling Dysfunctional telomeres in primary cells from Fanconi anemia FANCD2 patientsJoksic, IvanaVujic, DraganaGuc-Scekic, MarijaLeskovac, AndrejaPetrovic, SandraOjani, MaryamTrujillo Quintero, Juan PabloSurralles, Jordi|||0000-0002-4041-7519Zivkovic, MajaStankovic, AleksandraSlijepcevic, PedragJoksic, GordanaPrimary FA cellsTelomere dysfunctionExpression of TRF1 and TRF2Background: Fanconi anemia (FA) is characterized by sensitivity to DNA cross-linking agents, mild cellular, and marked clinical radio sensitivity. In this study we investigated telomeric abnormalities of non-immortalized primary cells (lymphocytes and fibroblasts) derived from FA patients of the FA-D2 complementation group, which provides a more accurate physiological assessment than is possible with transformed cells or animal models. Results: We analyzed telomere length, telomere dysfunction-induced foci (TIFs), sister chromatid exchanges (SCE), telomere sister chromatid exchanges (T-SCE), apoptosis and expression of shelterin components TRF1 and TRF2. FANCD2 lymphocytes exhibited multiple types of telomeric abnormalities, including premature telomere shortening, increase in telomeric recombination and aberrant telomeric structures ranging from fragile to long-string extended telomeres. The baseline incidence of SCE in FANCD2 lymphocytes was reduced when compared to control, but in response to diepoxybutane (DEB) the 2-fold higher rate of SCE was observed. In contrast, control lymphocytes showed decreased SCE incidence in response to DEB treatment. FANCD2 fibroblasts revealed a high percentage of TIFs, decreased expression of TRF1 and invariable expression of TRF2. The percentage of TIFs inversely correlated with telomere length, emphasizing that telomere shortening is the major reason for the loss of telomere capping function. Upon irradiation, a significant decrease of TIFs was observed at all recovery times. Surprisingly, a considerable percentage of TIF positive cells disappeared at the same time when incidence of γ-H2AX foci was maximal. Both FANCD2 leucocytes and fibroblasts appeared to die spontaneously at higher rate than control. This trend was more evident upon irradiation; the percentage of leucocytes underwent apoptosis was 2.59- fold higher than that in control, while fibroblasts exhibited a 2- h delay before entering apoptosis. Conclusion: The results of our study showed that primary cells originating from FA-D2 patients display shorten telomeres, elevated incidence of T-SCEs and high frequency of TIFs. Disappearance of TIFs in early response to irradiation represent distinctive feature of FANCD2 cells that should be examined further. 22012-01-0120122012-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/113422https://dx.doi.org/urn:doi:10.1186/2041-9414-3-6reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/3.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:1134222026-06-06T12:50:31Z
dc.title.none.fl_str_mv Dysfunctional telomeres in primary cells from Fanconi anemia FANCD2 patients
title Dysfunctional telomeres in primary cells from Fanconi anemia FANCD2 patients
spellingShingle Dysfunctional telomeres in primary cells from Fanconi anemia FANCD2 patients
Joksic, Ivana
Primary FA cells
Telomere dysfunction
Expression of TRF1 and TRF2
title_short Dysfunctional telomeres in primary cells from Fanconi anemia FANCD2 patients
title_full Dysfunctional telomeres in primary cells from Fanconi anemia FANCD2 patients
title_fullStr Dysfunctional telomeres in primary cells from Fanconi anemia FANCD2 patients
title_full_unstemmed Dysfunctional telomeres in primary cells from Fanconi anemia FANCD2 patients
title_sort Dysfunctional telomeres in primary cells from Fanconi anemia FANCD2 patients
dc.creator.none.fl_str_mv Joksic, Ivana
Vujic, Dragana
Guc-Scekic, Marija
Leskovac, Andreja
Petrovic, Sandra
Ojani, Maryam
Trujillo Quintero, Juan Pablo
Surralles, Jordi|||0000-0002-4041-7519
Zivkovic, Maja
Stankovic, Aleksandra
Slijepcevic, Pedrag
Joksic, Gordana
author Joksic, Ivana
author_facet Joksic, Ivana
Vujic, Dragana
Guc-Scekic, Marija
Leskovac, Andreja
Petrovic, Sandra
Ojani, Maryam
Trujillo Quintero, Juan Pablo
Surralles, Jordi|||0000-0002-4041-7519
Zivkovic, Maja
Stankovic, Aleksandra
Slijepcevic, Pedrag
Joksic, Gordana
author_role author
author2 Vujic, Dragana
Guc-Scekic, Marija
Leskovac, Andreja
Petrovic, Sandra
Ojani, Maryam
Trujillo Quintero, Juan Pablo
Surralles, Jordi|||0000-0002-4041-7519
Zivkovic, Maja
Stankovic, Aleksandra
Slijepcevic, Pedrag
Joksic, Gordana
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Primary FA cells
Telomere dysfunction
Expression of TRF1 and TRF2
topic Primary FA cells
Telomere dysfunction
Expression of TRF1 and TRF2
description Background: Fanconi anemia (FA) is characterized by sensitivity to DNA cross-linking agents, mild cellular, and marked clinical radio sensitivity. In this study we investigated telomeric abnormalities of non-immortalized primary cells (lymphocytes and fibroblasts) derived from FA patients of the FA-D2 complementation group, which provides a more accurate physiological assessment than is possible with transformed cells or animal models. Results: We analyzed telomere length, telomere dysfunction-induced foci (TIFs), sister chromatid exchanges (SCE), telomere sister chromatid exchanges (T-SCE), apoptosis and expression of shelterin components TRF1 and TRF2. FANCD2 lymphocytes exhibited multiple types of telomeric abnormalities, including premature telomere shortening, increase in telomeric recombination and aberrant telomeric structures ranging from fragile to long-string extended telomeres. The baseline incidence of SCE in FANCD2 lymphocytes was reduced when compared to control, but in response to diepoxybutane (DEB) the 2-fold higher rate of SCE was observed. In contrast, control lymphocytes showed decreased SCE incidence in response to DEB treatment. FANCD2 fibroblasts revealed a high percentage of TIFs, decreased expression of TRF1 and invariable expression of TRF2. The percentage of TIFs inversely correlated with telomere length, emphasizing that telomere shortening is the major reason for the loss of telomere capping function. Upon irradiation, a significant decrease of TIFs was observed at all recovery times. Surprisingly, a considerable percentage of TIF positive cells disappeared at the same time when incidence of γ-H2AX foci was maximal. Both FANCD2 leucocytes and fibroblasts appeared to die spontaneously at higher rate than control. This trend was more evident upon irradiation; the percentage of leucocytes underwent apoptosis was 2.59- fold higher than that in control, while fibroblasts exhibited a 2- h delay before entering apoptosis. Conclusion: The results of our study showed that primary cells originating from FA-D2 patients display shorten telomeres, elevated incidence of T-SCEs and high frequency of TIFs. Disappearance of TIFs in early response to irradiation represent distinctive feature of FANCD2 cells that should be examined further.
publishDate 2012
dc.date.none.fl_str_mv 2
2012-01-01
2012
2012-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/113422
https://dx.doi.org/urn:doi:10.1186/2041-9414-3-6
url https://ddd.uab.cat/record/113422
https://dx.doi.org/urn:doi:10.1186/2041-9414-3-6
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/3.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/3.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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