de Oliveira, Beatriz Cristina Dias, Shiburah, Mark Ewusi, Assis, Luiz Henrique Castro, Fontes, Veronica Silva, Bisetegn, Habtye, de Oliveira Passos, Arthur, de Oliveira, Leilane S, de Santis Alves, Cristiane, Ernst, Evan, Martienssen, Rob, Gallo-Francisco, Pedro Henrique, Giorgio, Selma, Batista, Marcos Meuser, de Nazaré Correia Soeiro, Maria, Menna-Barreto, Rubem Figueiredo Sadok, Aoki, Juliana Ide, Coelho, Adriano Cappellazzo, Cano, Maria Isabel Nogueira (August 2024) Leishmania major telomerase RNA knockout: From altered cell proliferation to decreased parasite infectivity. International Journal of Biological Macromolecules. p. 135150. ISSN 0141-8130
Abstract
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.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > telomerase |
| CSHL Authors: | |
| Communities: | CSHL labs > Martienssen lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 30 August 2024 |
| Date Deposited: | 03 Sep 2024 13:51 |
| Last Modified: | 03 Sep 2024 13:51 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41649 |
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