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1.
Genes Dev ; 34(23-24): 1619-1636, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33122293

RESUMEN

Mutations in the telomere-binding protein POT1 are associated with solid tumors and leukemias. POT1 alterations cause rapid telomere elongation, ATR kinase activation, telomere fragility, and accelerated tumor development. Here, we define the impact of mutant POT1 alleles through complementary genetic and proteomic approaches based on CRISPR interference and biotin-based proximity labeling, respectively. These screens reveal that replication stress is a major vulnerability in cells expressing mutant POT1, which manifests as increased telomere mitotic DNA synthesis at telomeres. Our study also unveils a role for the nuclear pore complex in resolving replication defects at telomeres. Depletion of nuclear pore complex subunits in the context of POT1 dysfunction increases DNA damage signaling, telomere fragility and sister chromatid exchanges. Furthermore, we observed telomere repositioning to the nuclear periphery driven by nuclear F-actin polymerization in cells with POT1 mutations. In conclusion, our study establishes that relocalization of dysfunctional telomeres to the nuclear periphery is critical to preserve telomere repeat integrity.


Asunto(s)
Replicación del ADN/genética , Poro Nuclear/patología , Proteínas de Unión a Telómeros/genética , Telómero/genética , Línea Celular Tumoral , Daño del ADN/genética , Humanos , Mitosis/genética , Mutación , Neoplasias/genética , Neoplasias/fisiopatología , Complejo Shelterina , Telómero/metabolismo , Proteínas de Unión a Telómeros/metabolismo
2.
EMBO J ; 40(2): e106696, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33346941

RESUMEN

Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA-derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine-tRNAGUA fragments in human cells-causing significant depletion of the precursor tRNA. Tyrosine-tRNAGUA depletion impaired translation of growth and metabolic genes enriched in cognate tyrosine codons. Depletion of tyrosine tRNAGUA or its translationally regulated targets USP3 and SCD repressed proliferation-revealing a dedicated tRNA-regulated growth-suppressive pathway for oxidative stress response. Tyrosine fragments are generated in a DIS3L2 exoribonuclease-dependent manner and inhibit hnRNPA1-mediated transcript destabilization. Moreover, tyrosine fragmentation is conserved in C. elegans. Thus, tRNA fragmentation can coordinately generate trans-acting small RNAs and functionally deplete a tRNA. Our findings reveal the existence of an underlying adaptive codon-based regulatory response inherent to the genetic code.


Asunto(s)
Codón/genética , Biosíntesis de Proteínas/genética , ARN de Transferencia/genética , Tirosina/genética , Animales , Caenorhabditis elegans/genética , Línea Celular , Proliferación Celular/genética , Células HEK293 , Humanos , Estrés Oxidativo/genética , Proteasas Ubiquitina-Específicas/genética
3.
Nat Rev Cancer ; 23(11): 746-761, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37814109

RESUMEN

Transfer RNAs (tRNAs) have been historically viewed as non-dynamic adaptors that decode the genetic code into proteins. Recent work has uncovered dynamic regulatory roles for these fascinating molecules. Advances in tRNA detection methods have revealed that specific tRNAs can become modulated upon DNA copy number and chromatin alterations and can also be perturbed by oncogenic signalling and transcriptional regulators in cancer cells or the tumour microenvironment. Such alterations in the levels of specific tRNAs have been shown to causally impact cancer progression, including metastasis. Moreover, sequencing methods have identified tRNA-derived small RNAs that influence various aspects of cancer progression, such as cell proliferation and invasion, and could serve as diagnostic and prognostic biomarkers or putative therapeutic targets in various cancers. Finally, there is accumulating evidence, including from genetic models, that specific tRNA synthetases - the enzymes responsible for charging tRNAs with amino acids - can either promote or suppress tumour formation. In this Review, we provide an overview of how deregulation of tRNAs influences cancer formation and progression.


Asunto(s)
Neoplasias , Humanos , Neoplasias/patología , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , Procesos Neoplásicos , Aminoácidos , Microambiente Tumoral
4.
Nat Cell Biol ; 24(3): 307-315, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35288656

RESUMEN

Tumourigenesis and cancer progression require enhanced global protein translation1-3. Such enhanced translation is caused by oncogenic and tumour-suppressive events that drive the synthesis and activity of translational machinery4,5. Here we report the surprising observation that leucyl-tRNA synthetase (LARS) becomes repressed during mammary cell transformation and in human breast cancer. Monoallelic genetic deletion of LARS in mouse mammary glands enhanced breast cancer tumour formation and proliferation. LARS repression reduced the abundance of select leucine tRNA isoacceptors, leading to impaired leucine codon-dependent translation of growth suppressive genes, including epithelial membrane protein 3 (EMP3) and gamma-glutamyltransferase 5 (GGT5). Our findings uncover a tumour-suppressive tRNA synthetase and reveal that dynamic repression of a specific tRNA synthetase-along with its downstream cognate tRNAs-elicits a downstream codon-biased translational gene network response that enhances breast tumour formation and growth.


Asunto(s)
Aminoacil-ARNt Sintetasas , Neoplasias de la Mama , Leucina-ARNt Ligasa , Aminoacil-ARNt Sintetasas/genética , Aminoacil-ARNt Sintetasas/metabolismo , Animales , Neoplasias de la Mama/genética , Codón/genética , Femenino , Humanos , Leucina-ARNt Ligasa/metabolismo , Glicoproteínas de Membrana , Ratones , ARN de Transferencia/metabolismo
5.
Biochim Biophys Acta Mol Cell Res ; 1867(12): 118846, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32910988

RESUMEN

Altered expression and/or localization of cysteine cathepsins is believed to involve in thyroid diseases including cancer. Here, we examined the localization of cathepsins B and V in human thyroid tissue sections of different pathological conditions by immunolabeling and morphometry. Cathepsin B was mostly found within endo-lysosomes as expected. In contrast, cathepsin V was detected within nuclei, predominantly in cells of cold nodules, follicular and papillary thyroid carcinoma tissue, while it was less often detected in this unusual localization in hot nodules and goiter tissue. To understand the significance of nuclear cathepsin V in thyroid cells, this study aimed to establish a cellular model of stable nuclear cathepsin V expression. As representative of a specific form lacking the signal peptide and part of the propeptide, N-terminally truncated cathepsin V fused to eGFP recapitulated the nuclear localization of endogenous cathepsin V throughout the cell cycle in Nthy-ori 3-1 cells. Interestingly, the N-terminally truncated cathepsin V-eGFP was more abundant in the nuclei during S phase. These findings suggested a possible contribution of nuclear cathepsin V forms to cell cycle progression. Indeed, we found that N-terminally truncated cathepsin V-eGFP expressing cells were more proliferative than those expressing full-length cathepsin V-eGFP or wild type controls. We conclude that a specific molecular form of cathepsin V localizes to the nucleus of thyroid epithelial and carcinoma cells, where it might involve in deregulated pathways leading to hyperproliferation. These findings highlight the necessity to better understand cathepsin trafficking in health and disease. In particular, cell type specificity of mislocalization of cysteine cathepsins, which otherwise act in a functionally redundant manner, seems to be important to understand their non-canonical roles in cell cycle progression.


Asunto(s)
Catepsinas/genética , Núcleo Celular/genética , Cisteína Endopeptidasas/genética , Células Epiteliales Tiroideas/metabolismo , Neoplasias de la Tiroides/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Lisosomas/genética , Glándula Tiroides/metabolismo , Neoplasias de la Tiroides/patología
6.
Cell Rep ; 15(10): 2170-2184, 2016 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-27239034

RESUMEN

Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis.


Asunto(s)
Carcinogénesis/metabolismo , Carcinogénesis/patología , Replicación del ADN , Proteínas de Unión al ADN/metabolismo , Estrés Fisiológico , Telómero/metabolismo , Secuencia de Aminoácidos , Animales , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Daño del ADN/genética , Reparación del ADN/genética , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Inestabilidad Genómica , Células Progenitoras Linfoides/metabolismo , Linfoma Cutáneo de Células T/genética , Linfoma Cutáneo de Células T/inmunología , Linfoma Cutáneo de Células T/patología , Ratones , Proteínas Mutantes/metabolismo , Mutación/genética , Unión Proteica , Complejo Shelterina , Proteínas de Unión a Telómeros , Timo/patología , Proteína p53 Supresora de Tumor/metabolismo
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