Leishmania major telomerase RNA knockout: From altered cell proliferation to decreased parasite infectivity
This study focuses on the biological impacts of deleting the telomerase RNA from Leishmania major (LeishTER), a parasite responsible for causing leishmaniases, for which no effective treatment or prevention is available. TER is a critical player in the telomerase ribonucleoprotein complex, containin...
| Autores: | , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | Brasil |
| Institución: | Universidade Estadual Paulista (UNESP) |
| Repositorio: | Repositório Institucional da UNESP |
| Idioma: | inglés |
| OAI Identifier: | oai:repositorio.unesp.br:11449/308665 |
| Acceso en línea: | http://dx.doi.org/10.1016/j.ijbiomac.2024.135150 https://hdl.handle.net/11449/308665 |
| Access Level: | acceso abierto |
| Palabra clave: | Altered cell proliferation Decreased infectivity capacity Leishmania spp. Telomerase RNA knockout and overexpression Telomere shortening TERRA upregulation |
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Brasil |
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| dc.title.none.fl_str_mv |
Leishmania major telomerase RNA knockout: From altered cell proliferation to decreased parasite infectivity |
| title |
Leishmania major telomerase RNA knockout: From altered cell proliferation to decreased parasite infectivity |
| spellingShingle |
Leishmania major telomerase RNA knockout: From altered cell proliferation to decreased parasite infectivity de Oliveira, Beatriz Cristina Dias [UNESP] Altered cell proliferation Decreased infectivity capacity Leishmania spp. Telomerase RNA knockout and overexpression Telomere shortening TERRA upregulation |
| title_short |
Leishmania major telomerase RNA knockout: From altered cell proliferation to decreased parasite infectivity |
| title_full |
Leishmania major telomerase RNA knockout: From altered cell proliferation to decreased parasite infectivity |
| title_fullStr |
Leishmania major telomerase RNA knockout: From altered cell proliferation to decreased parasite infectivity |
| title_full_unstemmed |
Leishmania major telomerase RNA knockout: From altered cell proliferation to decreased parasite infectivity |
| title_sort |
Leishmania major telomerase RNA knockout: From altered cell proliferation to decreased parasite infectivity |
| dc.creator.none.fl_str_mv |
de Oliveira, Beatriz Cristina Dias [UNESP] Shiburah, Mark Ewusi [UNESP] Assis, Luiz Henrique Castro [UNESP] Fontes, Veronica Silva [UNESP] Bisetegn, Habtye [UNESP] Passos, Arthur de Oliveira [UNESP] de Oliveira, Leilane S. [UNESP] Alves, Cristiane de Santis Ernst, Evan Martienssen, Rob Gallo-Francisco, Pedro Henrique Giorgio, Selma Batista, Marcos Meuser Soeiro, Maria de Nazaré Correia Menna-Barreto, Rubem Figueiredo Sadok Aoki, Juliana Ide Coelho, Adriano Cappellazzo Cano, Maria Isabel Nogueira [UNESP] |
| author |
de Oliveira, Beatriz Cristina Dias [UNESP] |
| author_facet |
de Oliveira, Beatriz Cristina Dias [UNESP] Shiburah, Mark Ewusi [UNESP] Assis, Luiz Henrique Castro [UNESP] Fontes, Veronica Silva [UNESP] Bisetegn, Habtye [UNESP] Passos, Arthur de Oliveira [UNESP] de Oliveira, Leilane S. [UNESP] Alves, Cristiane de Santis Ernst, Evan Martienssen, Rob Gallo-Francisco, Pedro Henrique Giorgio, Selma Batista, Marcos Meuser Soeiro, Maria de Nazaré Correia Menna-Barreto, Rubem Figueiredo Sadok Aoki, Juliana Ide Coelho, Adriano Cappellazzo Cano, Maria Isabel Nogueira [UNESP] |
| author_role |
author |
| author2 |
Shiburah, Mark Ewusi [UNESP] Assis, Luiz Henrique Castro [UNESP] Fontes, Veronica Silva [UNESP] Bisetegn, Habtye [UNESP] Passos, Arthur de Oliveira [UNESP] de Oliveira, Leilane S. [UNESP] Alves, Cristiane de Santis Ernst, Evan Martienssen, Rob Gallo-Francisco, Pedro Henrique Giorgio, Selma Batista, Marcos Meuser Soeiro, Maria de Nazaré Correia Menna-Barreto, Rubem Figueiredo Sadok Aoki, Juliana Ide Coelho, Adriano Cappellazzo Cano, Maria Isabel Nogueira [UNESP] |
| author2_role |
author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (UNESP) Council for Scientific and Industrial Research (CSIR-ARI) Wollo University Howard Hughes Medical Institute/Cold Spring Harbor Laboratory Universidade Estadual de Campinas (UNICAMP) Oswaldo Cruz Foundation |
| dc.subject.por.fl_str_mv |
Altered cell proliferation Decreased infectivity capacity Leishmania spp. Telomerase RNA knockout and overexpression Telomere shortening TERRA upregulation |
| topic |
Altered cell proliferation Decreased infectivity capacity Leishmania spp. Telomerase RNA knockout and overexpression Telomere shortening TERRA upregulation |
| description |
This study focuses on the biological impacts of deleting the telomerase RNA from Leishmania major (LeishTER), a parasite responsible for causing leishmaniases, for which no effective treatment or prevention is available. TER is a critical player in the telomerase ribonucleoprotein complex, containing the template sequence copied by the reverse transcriptase component during telomere elongation. The success of knocking out both LeishTER alleles was confirmed, and no off-targets were detected. LmTER−/− cells share similar characteristics with other TER-depleted eukaryotes, such as altered growth patterns and partial G0/G1 cell cycle arrest in early passages, telomere shortening, and elevated TERRA expression. They also exhibit increased γH2A phosphorylation, suggesting that the loss of LeishTER induces DNA damage signaling. Moreover, pro-survival autophagic signals and mitochondrion alterations were shown without any detectable plasma membrane modifications. LmTER−/− retained the ability to transform into metacyclics, but their infectivity capacity was compromised. Furthermore, the overexpression of LeishTER was also deleterious, inducing a dominant negative effect that led to telomere shortening and growth impairments. These findings highlight TER's vital role in parasite homeostasis, opening discussions about its potential as a drug target candidate against Leishmania. |
| publishDate |
2024 |
| dc.date.none.fl_str_mv |
2024-11-01 2025-04-29T20:13:19Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
| dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.ijbiomac.2024.135150 International Journal of Biological Macromolecules, v. 279. 1879-0003 0141-8130 https://hdl.handle.net/11449/308665 10.1016/j.ijbiomac.2024.135150 2-s2.0-85203056214 |
| url |
http://dx.doi.org/10.1016/j.ijbiomac.2024.135150 https://hdl.handle.net/11449/308665 |
| identifier_str_mv |
International Journal of Biological Macromolecules, v. 279. 1879-0003 0141-8130 10.1016/j.ijbiomac.2024.135150 2-s2.0-85203056214 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
International Journal of Biological Macromolecules |
| dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
| instname_str |
Universidade Estadual Paulista (UNESP) |
| instacron_str |
UNESP |
| institution |
UNESP |
| reponame_str |
Repositório Institucional da UNESP |
| collection |
Repositório Institucional da UNESP |
| repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
| repository.mail.fl_str_mv |
repositoriounesp@unesp.br |
| _version_ |
1853671995927953408 |
| spelling |
Leishmania major telomerase RNA knockout: From altered cell proliferation to decreased parasite infectivityAltered cell proliferationDecreased infectivity capacityLeishmania spp.Telomerase RNA knockout and overexpressionTelomere shorteningTERRA upregulationThis study focuses on the biological impacts of deleting the telomerase RNA from Leishmania major (LeishTER), a parasite responsible for causing leishmaniases, for which no effective treatment or prevention is available. TER is a critical player in the telomerase ribonucleoprotein complex, containing the template sequence copied by the reverse transcriptase component during telomere elongation. The success of knocking out both LeishTER alleles was confirmed, and no off-targets were detected. LmTER−/− cells share similar characteristics with other TER-depleted eukaryotes, such as altered growth patterns and partial G0/G1 cell cycle arrest in early passages, telomere shortening, and elevated TERRA expression. They also exhibit increased γH2A phosphorylation, suggesting that the loss of LeishTER induces DNA damage signaling. Moreover, pro-survival autophagic signals and mitochondrion alterations were shown without any detectable plasma membrane modifications. LmTER−/− retained the ability to transform into metacyclics, but their infectivity capacity was compromised. Furthermore, the overexpression of LeishTER was also deleterious, inducing a dominant negative effect that led to telomere shortening and growth impairments. These findings highlight TER's vital role in parasite homeostasis, opening discussions about its potential as a drug target candidate against Leishmania.ASCRS Research FoundationCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Department of Chemical and Biological Sciences Biosciences Institute São Paulo State University (UNESP), Sao PauloAnimal Research Institute Council for Scientific and Industrial Research (CSIR-ARI)Department of Medical Laboratory Sciences College of Medicine and Health Sciences Wollo UniversityHoward Hughes Medical Institute/Cold Spring Harbor LaboratoryDepartment of Animal Biology Biology Institute University of Campinas (UNICAMP), Sao PauloCellular Biology Laboratory Oswaldo Cruz Institute Oswaldo Cruz Foundation, Rio de JaneiroDepartment of Chemical and Biological Sciences Biosciences Institute São Paulo State University (UNESP), Sao PauloCNPq: 163895/2022-8FAPESP: 2016/21171-6FAPESP: 2018/04375-2FAPESP: 2019/11061-7FAPESP: 2019/25985-6FAPESP: 2020/00316-1FAPESP: 2021/04253-7CNPq: 302433/2019-8Universidade Estadual Paulista (UNESP)Council for Scientific and Industrial Research (CSIR-ARI)Wollo UniversityHoward Hughes Medical Institute/Cold Spring Harbor LaboratoryUniversidade Estadual de Campinas (UNICAMP)Oswaldo Cruz Foundation2025-04-29T20:13:19Z2024-11-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.ijbiomac.2024.135150International Journal of Biological Macromolecules, v. 279.1879-00030141-8130https://hdl.handle.net/11449/30866510.1016/j.ijbiomac.2024.1351502-s2.0-85203056214Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengInternational Journal of Biological Macromoleculesinfo:eu-repo/semantics/openAccessde Oliveira, Beatriz Cristina Dias [UNESP]Shiburah, Mark Ewusi [UNESP]Assis, Luiz Henrique Castro [UNESP]Fontes, Veronica Silva [UNESP]Bisetegn, Habtye [UNESP]Passos, Arthur de Oliveira [UNESP]de Oliveira, Leilane S. [UNESP]Alves, Cristiane de SantisErnst, EvanMartienssen, RobGallo-Francisco, Pedro HenriqueGiorgio, SelmaBatista, Marcos MeuserSoeiro, Maria de Nazaré CorreiaMenna-Barreto, Rubem Figueiredo SadokAoki, Juliana IdeCoelho, Adriano CappellazzoCano, Maria Isabel Nogueira [UNESP]2025-04-30T13:24:04Zoai:repositorio.unesp.br:11449/308665Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestrepositoriounesp@unesp.bropendoar:29462025-04-30T13:24:04Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
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15.301603 |