Human Chromosome Telomeres

Barbé-Tuana, Florencia Marı́a; Grün, Lucas Kich; Pierdoná, Vinícius; Oliveira, Beatriz C. D. de; Paiva, Stephany C.; Shiburah, Mark E.; Silva, Vítor Luiz da; Morea, Edna Gicela Ortiz; Fontes, Veronica S.; Cano, Maria Isabel Nogueira

doi:10.1007/978-3-030-73151-9_7

Cited by 2 publications

(3 citation statements)

References 251 publications

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“…Telomeres are essential to most eukaryotic chromosomes, including Leishmania spp., and are crucial to genome stability and survival [11][12][13][14][15][16]. A proper understanding of the mechanisms and roles of telomeres in parasite survival would provide answers in the search for new and parasite-specific drug targets [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Ablation of telomerase reverse transcriptase inLeishmania majorresults in a senescent-like phenotype and loss of infectivity

Shiburah,

de Oliveira,

Bisetegn

et al. 2023

Preprint

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The lack of efficient human vaccines and effective nontoxic drugs for leishmaniasis necessitates a search for new therapeutic targets. The telomere environment could provide potential targets against leishmaniasis. TERT, the telomerase reverse transcriptase component, has been on the radar for new therapeutic options against several diseases for more than two decades. In this study, we constructed a full deletion (LmTERT-/-) and an ORF disruption (LmN420) of the gene encoding the TERT component ofLeishmania major.LmTERT-/- andLmN420 parasites showed replicative and proliferative defects, growth impairment, cell cycle alterations, increased DNA damage, and progressive telomere shortening. Blockage of parasite altruism and the presence of autophagosomes characteristic of a senescent-like phenotype were also detected.LmTERT-/- andLmN420 parasites caused either micro lesion development or no visible lesions in mouse footpads and reduced infectivity in macrophages. While our checks to see if telomere erosion had reached theSCGgenes involved in lipophosphoglycan modification showed no changes, our proteomic assessment revealed a downregulation of a metacyclic-associated protein. Complementation of the knockout lineages using the WTLmTERT restored some of the lost phenotypes. Therefore, we speculate that the pleiotropic effects of the loss ofLmTERT advance the case for using it as a drug target against the parasite.

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Section: Introductionmentioning

confidence: 99%

Ablation of telomerase reverse transcriptase inLeishmania majorresults in a senescent-like phenotype and loss of infectivity

Shiburah,

de Oliveira,

Bisetegn

et al. 2023

Preprint

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“…In addition, it contains the pseudoknot and the Stem Terminus Element (STE) (called CR4/CR5 in humans and Helix IV in trypanosomatids) [27,28]. In some organisms, TER may contain additional domains, such as the H/ACA box in mammals and the C/D box in flagellates like trypanosomatids [13,29,30].…”

Section: Introductionmentioning

confidence: 99%

“…Telomeres consist of tandemly repeated DNA sequences and exhibit a G-rich strand that extends beyond the complementary C-rich strand, forming a 3’ G-overhang [11,12]. In vertebrates and trypanosomatids, including Leishmania , the telomeres comprise 5’ TTAGGG 3’ repeated sequences [13,14,15].…”

Section: Introductionmentioning

confidence: 99%

The impact of knocking out theLeishmania majortelomerase RNA (LeishTER): from altered cell proliferation to decreased parasite infectivity

de Oliveira,

Shiburah,

Assis

et al. 2023

Preprint

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The telomerase RNA, TER, is an intrinsic component of the telomerase ribonucleoprotein complex. It contains the telomere template sequence copied by the enzyme during telomere elongation. This unique molecule shows divergent nucleotide sequences but a more conserved secondary structure containing domains involved with telomerase assembly and biogenesis. The present work aims to characterize the biological roles played by theLeishmaniaTER component (LeishTER) in parasite homeostasis. We generated double knockout (LmTER-/-) parasites, which showed a distinct growth pattern at early passages, characterized by lower density and an extended stationary phase compared to the control. Although this pattern normalized after multiple in vitro passages, ablation ofLeishTER affected cell division and proliferation, with cells arrested at the G0/G1 phase. Progressive telomere shortening was also observed during continuous passages, along with a reduction in the expression of TERRA29. Complementation with the episomal expression ofLeishTER did not restore telomere length to the control levels, corroborating preliminary results showing that the overexpression of TER has a dominant negative effect on parasite lifespan.LmTER-/-also presented a higher percentage of gamma-H2A phosphorylation, likely due to stalled replication forks since no DNA damage was observed. Also, no plasma membrane modifications were detected, but pro-survival autophagic signals were present. Intriguingly,LmTER-/-retained the ability to transform into metacyclic forms, although its in vitro infectivity and growth inside the host cell were compromised. Together, these results highlight the importance of TER in parasite lifespan and open a discussion about its potential as a drug target againstLeishmania.

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Human Chromosome Telomeres

Cited by 2 publications

References 251 publications

Ablation of telomerase reverse transcriptase inLeishmania majorresults in a senescent-like phenotype and loss of infectivity

Ablation of telomerase reverse transcriptase inLeishmania majorresults in a senescent-like phenotype and loss of infectivity

The impact of knocking out theLeishmania majortelomerase RNA (LeishTER): from altered cell proliferation to decreased parasite infectivity

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