» Dra. Anabella Srebrow

Líneas de investigación

Signals to and from the splicing machinery

Since we know that the number of genes in higher organisms cannot explain their complexity, the understanding about the regulation of post-transcriptional and post-translational processes responsible for generating proteomic diversity has become of paramount importance. Moreover, the more we learn about the mechanisms operating at different steps of gene expression, the more we realize the interconnectedness of those steps and thus the need for an integrated view of this field. In this context, the search for molecules that concertedly regulate different processes, from transcription to protein function, turn out to be extremely relevant.
Our group studies the influence of the cellular microenvironment on alternative splicing regulation. We concentrate on the signaling pathways that link extracellular cues triggered by epithelial-stromal and cell-extracellular matrix interactions with the splicing machinery, unraveling cis-acting sequences within the pre-mRNA and trans-acting factors involved. To this end, we focus on mammary epithelial morphogenesis and function as well as its oncogenic transformation, taking advantage of existing cell culture models that recapitulate many aspects of mammary gland normal and pathological development. In this context, we have analyzed alternative splicing patterns of fibronectin and Rac1 pre-mRNAs. We found that the activation of a given signaling cascade regulates the activity of two splicing factors of the SR family of proteins, simultaneously altering both nuclear and cytoplasmic steps of RNA metabolism: alternative splicing and translation. These results suggest that this concerted effort could increase both the speed and strength of the cellular response to a given extracellular stimulation.
By serendipity, we found that the SR protein SF2/ASF (recently renamed “SRSF1”) regulates SUMO conjugation, a fundamental protein post-translational modification. These results add a new component to the SUMO pathway, unraveling an unforeseen role for SR proteins, traditionally known as splicing factors, and opening up provocative questions regarding the connection between splicing and SUMOylation. We are interesting in exploring this putative connection, expanding the knowledge about the regulation of pre-mRNA processing by SUMO conjugation and about the interplay between different tiers of gene expression regulation.

 

Publicaciones de los últimos 5 años:

Berta Pozzi*, Pablo Mammi*, Laureano Bragado, Luciana Giono, Anabella Srebrow. “When SUMO met splicing”. RNA Biology 2018;15(6):689-695 doi: 10.1080/15476286.2018.1457936.
* Autores con igual contribución

Pozzi B, Bragado L*, Will CL*, Mammi P, Risso G, Urlaub H, Lührmann R, Srebrow A. “SUMO conjugation to spliceosomal proteins is required for efficient pre-mRNA splicing”. Nucleic Acids Res. 45(11):6729–6745 (2017).
* Autores con igual contribución

Federico De Maio*, Guillermo Risso*, Gabriel Iglesias*, Priya Shah, Berta Pozzi, Leopoldo Gebhard, Pablo Mammi, Estefania Mancini, Marcelo Yanovsky, Raul Andino, NevanKrogan, Anabella Srebrow#, and Andrea Gamarnik#. “The Dengue Virus NS5 Protein Intrudes in the Cellular Spliceosome and Modulates Splicing”. Plos Pathogens 12(8):e1005841 (2016).
* Autores con igual contribución – # “co-autores corresponsales”
Risso G, Blaustein M, Pozzi B, Mammi P and Srebrow A. “Akt/PKB: one kinase, many modifications”. Biochemical Journal 468, 203-214 (2015).
Risso G, Pelisch F, Pozzi B, Mammi P, Blaustein M, Colman-Lerner A,Srebrow A. “Modification of Akt by SUMO conjugation regulates alternative splicing and cell cycle”. Cell Cycle (2013) 12(19):3165-74.
Pelisch F, Risso G.  and Srebrow A. “RNA metabolism and ubiquitin/ubiquitin-like modifications collide”. Briefings in Functional Genomics  12, 66-71 (2013).
Pelisch F, Pozzi B, Risso G, Muñoz M and Srebrow A. “DNA Damage-Induced Heterogeneous Nuclear Ribonucleoprotein K SUMOylation Regulates p53 Transcriptional Activation. Journal of Biological Chemistry 287, 30789–30799 (2012).
Risso G, Pelisch F, Quaglino A, Pozz Bi and Srebrow A. “Regulating the regulators: SR proteins under scrutiny”. IUBMB Life 64, 809-816 (2012).
Pelisch F, Khauv D, Risso G, Stallings-Mann M, Blaustein M,  Quadrana L, Radisky DC, and Srebrow A. “Involvement of hnRNP A1 in the Matrix Metalloprotease-3-Dependent Regulation of Rac1 Pre-mRNA Splicing”. Journal of Cellular Biochemistry 113, 2319-29 (2012).
Pelisch F, Gerez J, Druker J, Schor I E, Muñoz M, Risso G,Petrillo E, Westman BJ, Lamond A I, Arzt E, and Srebrow A. “The Serine-Arginine Rich Protein SF2/ASF Regulates Protein SUMOylation”. Proceedings of the National Academy of Sciences USA 107,16119-16124 (2010).

Proyectos financiados en vigencia

  • “Reprogramación de la maquinaria de splicing durante la infección de células humanas con el virus del dengue”. PICT 2015 (1731) de ANPCyT.
  • “Conectando la maquinaria de splicing con la cascada de conjugación de SUMO”. UBACyT para grupos consolidados (2018-2021), código 20020170100045BA.”
  • “Explorando la conexión entre SUMO y splicing”. PICT 2017 (0111) de ANPCyT, para equipo de trabajo.”

Últimos premios recibidos

2011- Mención Nacional L’Oreal-UNESCO-CONICET “Por la Mujer en la Ciencia”. Proyecto de Investigación: “Señales hacia y desde la maquinaria de procesamiento del ARN mensajero. Splicing alternativo y modificaciones post- traduccionales en un contexto fisio-patológico”.

Doctorados dirigidos

  • Matías Blaustein
  • Federico Pelisch
  • Guillermo Risso
  • Berta Pozzi
  • Pablo Mammi

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Integrantes del Grupo

INVESTIGADOR A CARGO

Dra. Anabella Srebrow

Dra. Anabella Srebrow
Profesora Adjunta UBA
Investigadora Principal (CONICET)

PubMed

Investigaciones publicadas
en PubMed


BECARIOS POSTDOCTORALES


BECARIOS

Dr. Pablo Mammi

Dr. Pablo Mammi
Dr. Pablo Mammi
Becario Post-Doctoral

Lic. Laureano Bragado

Lic. Laureano Bragado,
Becario Doctoral CONICET

Lic. Laureano Bragado

Nicolas Gaioli,
Estudiante de grado

Lic. Laureano Bragado

Melina Magalnik,
Estudiante de grado

Lic. Laureano Bragado

Dra. Rita Vaz-Drago,
Visitante Post-Doctoral