19 research outputs found
Polo-like kinase 1 inhibition as a therapeutic approach to selectively target BRCA1-deficient cancer cells by synthetic lethality induction
Purpose: BRCA1 and BRCA2 deficiencies are widespread drivers of human cancers that await the development of targeted therapies. We aimed to identify novel synthetic lethal relationships with therapeutic potential using BRCA-deficient isogenic backgrounds. Experimental Design: We developed a phenotypic screening technology to simultaneously search for synthetic lethal (SL) interactions in BRCA1- and BRCA2-deficient contexts. For validation, we developed chimeric spheroids and a dualtumor xenograft model that allowed the confirmation of SL induction with the concomitant evaluation of undesired cytotoxicity on BRCA-proficient cells. To extend our results using clinical data, we performed retrospective analysis on The Cancer Genome Atlas (TCGA) breast cancer database. Results: The screening of a kinase inhibitors library revealed that Polo-like kinase 1 (PLK1) inhibition triggers strong SL induction in BRCA1-deficient cells. Mechanistically, we found no connection between the SL induced by PLK1 inhibition and PARP inhibitors. Instead, we uncovered that BRCA1 downregulation and PLK1 inhibition lead to aberrant mitotic phenotypes with altered centrosomal duplication and cytokinesis, which severely reduced the clonogenic potential of these cells. The penetrance of PLK1/BRCA1 SL interaction was validated using several isogenic and nonisogenic cellular models, chimeric spheroids, and mice xenografts. Moreover, bioinformatic analysis revealed high-PLK1 expression in BRCA1-deficient tumors, a phenotype that was consistently recapitulated by inducing BRCA1 deficiency in multiple cell lines as well as in BRCA1-mutant cells. Conclusions: We uncovered an unforeseen addiction of BRCA1-deficient cancer cells to PLK1 expression, which provides a new means to exploit the therapeutic potential of PLK1 inhibitors in clinical trials, by generating stratification schemes that consider this molecular trait in patient cohorts.Fil: Carbajosa González, Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Pansa, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Paviolo, Natalia Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación Instituto Leloir; ArgentinaFil: Castellaro, Andrés Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Andino, Diego Leonardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas. Universidad Católica de Córdoba. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas; ArgentinaFil: Nigra, Ayelén Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: García, Iris Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Racca, Ana Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Rodriguez, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Angiolini, Virginia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Guantay, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Villafañez, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Federico, Maria Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Rodríguez, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Caputto, Beatriz Leonor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Drewes, Gerard. Cellzome AG; AlemaniaFil: Madauss, Kevin P.. Global Observatory on Health Research and Development; Estados UnidosFil: Gloger, Israel. Global Observatory on Health Research and Development; Estados UnidosFil: Fernandez, Elmer Andres. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas. Universidad Católica de Córdoba. Centro de Investigación y Desarrollo en Inmunología y Enfermedades Infecciosas; ArgentinaFil: Gil, German Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Bocco, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Soria, Ramiro Gaston. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentin
Author correction: One sixth of Amazonian tree diversity is dependent on river floodplains
In the version of the article initially published, the affiliation of Edgardo Manuel Latrubesse was incorrect and has now been amended to Environmental Sciences Graduate Program-CIAMB, Federal University of Goiás, Goiânia, Brazil in the HTML and PDF versions of the article
One sixth of Amazonian tree diversity is dependent on river floodplains
Amazonia’s floodplain system is the largest and most biodiverse on Earth. Although forests are crucial to the ecological integrity of floodplains, our understanding of their species composition and how this may differ from surrounding forest types is still far too limited, particularly as changing inundation regimes begin to reshape floodplain tree communities and the critical ecosystem functions they underpin. Here we address this gap by taking a spatially explicit look at Amazonia-wide patterns of tree-species turnover and ecological specialization of the region’s floodplain forests. We show that the majority of Amazonian tree species can inhabit floodplains, and about a sixth of Amazonian tree diversity is ecologically specialized on floodplains. The degree of specialization in floodplain communities is driven by regional flood patterns, with the most compositionally differentiated floodplain forests located centrally within the fluvial network and contingent on the most extraordinary flood magnitudes regionally. Our results provide a spatially explicit view of ecological specialization of floodplain forest communities and expose the need for whole-basin hydrological integrity to protect the Amazon’s tree diversity and its function
One sixth of Amazonian tree diversity is dependent on river floodplains
Amazonia’s floodplain system is the largest and most biodiverse on Earth. Although forests are crucial to the ecological integrity of floodplains, our understanding of their species composition and how this may differ from surrounding forest types is still far too limited, particularly as changing inundation regimes begin to reshape floodplain tree communities and the critical ecosystem functions they underpin. Here we address this gap by taking a spatially explicit look at Amazonia-wide patterns of tree-species turnover and ecological specialization of the region’s floodplain forests. We show that the majority of Amazonian tree species can inhabit floodplains, and about a sixth of Amazonian tree diversity is ecologically specialized on floodplains. The degree of specialization in floodplain communities is driven by regional flood patterns, with the most compositionally differentiated floodplain forests located centrally within the fluvial network and contingent on the most extraordinary flood magnitudes regionally. Our results provide a spatially explicit view of ecological specialization of floodplain forest communities and expose the need for whole-basin hydrological integrity to protect the Amazon’s tree diversity and its function
Análisis de la distribución de potenciales cuádruplex de Guanina (PQS) en el genoma de tripanosomátidos y su posible relación con el control de la expresión génica.
Los tripanosomátidos son una familia de eucariotas unicelulares con especies causantes de
importantes enfermedades en el ser humano. Los genes de estos organismos suelen organizarse en
lo que se conoce como unidades de transcripción policistrónica (PTUs), consistente en un grupo de
genes (y secuencias intergénicas) adyacentes en la misma hebra, que se transcriben en forma
conjunta dando lugar a una única molécula de ARN (ARN policistrónico). Los ARNm maduros son
producidos a partir de los ARN policistrónicos mediante un proceso de maduración que incluye el
fenómeno de trans-splicing y poliadenilación. Actualmente se conocen pocos detalles sobre los
mecanismos de regulación de la expresión génica tanto a nivel transcripcional (inicio y terminación
de la síntesis de los ARN policistrónicos) como post-transcripcional (maduración, estabilidad y
traducción de los ARNm).
Los cuádruples de guanina son estructuras secundarias del ADN o ARN formadas en
regiones ricas en guaninas. Se ha descrito la importancia de estas estructuras en la regulación de la
expresión génica en diversos organismos.
En el presente trabajo se realizó un análisis bioinformático de la frecuencia y distribución de
cuádruples putativos de guanina (PQSs) en los genomas de distintas especies de Leishmania y
Trypanosoma, a fin de evaluar su posible impacto en la regulación de la expresión génica a nivel
transcripcional y post-transcripcional.
En Trypanosoma se observó una densidad baja de PQSs a nivel genómico con un patrón
poco claro entre las distintas especies. Por otro lado, en Leishmania se observó una mayor densidad
de PQSs a nivel genómico, con una distribución bien definida y similar entre las tres especies
analizadas. En este último género, la densidad de PQSs aumenta en la hebra molde de la región
adyacente al extremo terminal de las PTUs, por lo cual es posible que los cuádruples de guanina
puedan estar vinculados a la terminación de la transcripción. Al analizar la distribución de PQSs
dentro de las PTUs de ambos géneros, se observó una diferencia muy marcada en la densidad de
PQSs entre las secuencias génicas e intergénicas (con una muy baja densidad de PQSs en las
primeras en relación a las segundas). Esto podría ser indicio de algún rol de los cuádruples de
guanina en las etapas maduración, estabilidad y/o traducción del ARNm.Trypanosomatids are a family of unicellular eukaryotes including species that cause
important diseases in humans. Genes of these organisms are usually organized in polycistronic
transcription units (PTUs). PTUs consist on a group of genes (and intergenic sequences) that are
located in tandem in the same strand. They are transcribed together to form a single molecule of
RNA (polycistronic RNA). Mature mRNAs are produced from polycistronic RNAs through a
maturation process that includes the phenomenon of trans-splicing and polyadenylation. Currently,
few details are known about the mechanisms of regulation of gene expression both at the
transcriptional level (initiation and termination of polycistronic RNA synthesis) and posttranscriptional
level (maturation, stability and translation of mRNAs).
Guanine quadruplexes are secondary structures of DNA or RNA which are formed in
regions rich in guanines. The importance of these structures in the regulation of gene expression in
various organisms has been described.
In order to evaluate the possible impact of guanine quadruplexes on the regulation of gene
expression at transcriptional and post-transcriptional level in Trypanosomatids, we performed a
bioinformatic analysis of the frequency and distribution of putative guanine quadruplexes (PQSs) in
the genomes of different species of Leishmania and Trypanosoma.
We observed a low density of PQSs in Trypanosoma genome, with an unclear pattern among
the different species. On the other hand, we identified a higher density of PQSs in Leishmania
genome with a well defined and similar distribution among the three species analyzed. In
Leishmania genus, the density of PQSs increases in the region adjacent to the terminal end of the
PTUs in the template strand. For that reason, we propose that guanine quadruplexes may be linked
to the termination of transcription. When we analyze the distribution of PQSs within the PTUs of
both genera, we observed a very marked difference in the density of PQSs between the gene and
intergenic sequences (with a very low density of PQSs in the former in relation to the latter). This
may indicate a role of guanine quadruplexes in maturation, stability and / or translation of the
mRNA.Fil: Apellido, Nombre. Universidad Nacional de Rosario. Facultad de Ciencias Agrarias; ArgentinaFil: Andino, Diego Leonardo. Universidad Nacional de Rosario. Facultad de Ciencias Agrarias; Argentin
One sixth of Amazonian tree diversity is dependent on river floodplains
Amazonia's floodplain system is the largest and most biodiverse on Earth. Although forests are crucial to the ecological integrity of floodplains, our understanding of their species composition and how this may differ from surrounding forest types is still far too limited, particularly as changing inundation regimes begin to reshape floodplain tree communities and the critical ecosystem functions they underpin. Here we address this gap by taking a spatially explicit look at Amazonia-wide patterns of tree-species turnover and ecological specialization of the region's floodplain forests. We show that the majority of Amazonian tree species can inhabit floodplains, and about a sixth of Amazonian tree diversity is ecologically specialized on floodplains. The degree of specialization in floodplain communities is driven by regional flood patterns, with the most compositionally differentiated floodplain forests located centrally within the fluvial network and contingent on the most extraordinary flood magnitudes regionally. Our results provide a spatially explicit view of ecological specialization of floodplain forest communities and expose the need for whole-basin hydrological integrity to protect the Amazon's tree diversity and its function
One sixth of Amazonian tree diversity is dependent on river floodplains
Amazonia’s floodplain system is the largest and most biodiverse on Earth. Although forests are crucial to the ecological integrity of floodplains, our understanding of their species composition and how this may differ from surrounding forest types is still far too limited, particularly as changing inundation regimes begin to reshape floodplain tree communities and the critical ecosystem functions they underpin. Here we address this gap by taking a spatially explicit look at Amazonia-wide patterns of tree-species turnover and ecological specialization of the region’s floodplain forests. We show that the majority of Amazonian tree species can inhabit floodplains, and about a sixth of Amazonian tree diversity is ecologically specialized on floodplains. The degree of specialization in floodplain communities is driven by regional flood patterns, with the most compositionally differentiated floodplain forests located centrally within the fluvial network and contingent on the most extraordinary flood magnitudes regionally. Our results provide a spatially explicit view of ecological specialization of floodplain forest communities and expose the need for whole-basin hydrological integrity to protect the Amazon’s tree diversity and its function
Recommended from our members
One sixth of Amazonian tree diversity is dependent on river floodplains.
Funder: PRONEX-MCT/CNPq/FAPEAM “Tipologias alágaveis 2007”,Universal (479599/2008-4) and PELD/MAUA Áreas Úmidas, additional funding was provided by the ATTO Project (German Federal Ministry of Education and Research, BMBF funds 01LK1602F, and 01LK2101D, Brazilian Ministry of Science, Technology, Innovation and Communication; FINEP/MCTIC contract 01.11.01248.00), UEA and FAPEAM, LBA/INPA and SDS/CEUC/RDS-Uatumã, and the EU Project BiodivERsA—Clambio (BMBF 16LC2025A);Funder: CNPq/CAPES/FAPS/BC-Newton Fund #441244/2016-5 and FAPEMAT/0589267/2016Funder: “Investissement d’Avenir” grant managed by the Agence Nationale de la Recherche (CEBA: ANR-10-LABX-25-01);Funder: CNPQ Grant 308040/2017-1Funder: PVE - MEC/MCTI/CAPES/CNPq/FAPs Reference #407232/2013-3 -Funder: MCT/CNPq/CT-INFRA/GEOMA #550373/2010-1 and # 457515/2012-0 CAPES/PDSE # 88881.135761/2016-01 CAPES/Fapespa #1530801Funder: MCT/CNPq/CT-INFRA/GEOMA #550373/2010-1 and # 457515/2012-0Funder: PVE - MEC/MCTI/CAPES/CNPq/FAPs Reference #407232/2013-3Funder: National Science Foundation grant DEB-1556338Funder: FAPESP grant 2016/25086-3Funder: FAPESP 95/3058-0 - CRS 068/96 WWF Brasil - The Body ShopAmazonia's floodplain system is the largest and most biodiverse on Earth. Although forests are crucial to the ecological integrity of floodplains, our understanding of their species composition and how this may differ from surrounding forest types is still far too limited, particularly as changing inundation regimes begin to reshape floodplain tree communities and the critical ecosystem functions they underpin. Here we address this gap by taking a spatially explicit look at Amazonia-wide patterns of tree-species turnover and ecological specialization of the region's floodplain forests. We show that the majority of Amazonian tree species can inhabit floodplains, and about a sixth of Amazonian tree diversity is ecologically specialized on floodplains. The degree of specialization in floodplain communities is driven by regional flood patterns, with the most compositionally differentiated floodplain forests located centrally within the fluvial network and contingent on the most extraordinary flood magnitudes regionally. Our results provide a spatially explicit view of ecological specialization of floodplain forest communities and expose the need for whole-basin hydrological integrity to protect the Amazon's tree diversity and its function