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IRB (Institute for Research in Biomedicine)

IRB (Institute for Research in Biomedicine)

El IRB Barcelona es un centro de investigación de primer nivel dedicado a estudiar cuestiones fundamentales de la salud y las enfermedades humanas. El IRB Barcelona fue fundado en octubre de 2005 por la Generalitat de Catalunya y la Universidad de Barcelona, y está situado en el Parque Científico de Barcelona. C/ Baldiri Reixac 10. 08028 Barcelona. http://www.irbbarcelona.org

El “corrector del ADN” es más eficiente en las regiones más relevantes del genoma

Fuente: IRB | Publicado: 09-11-2017
Un estudio publicado por el IRB Barcelona en Nature Genetics demuestra que el sistema de vigilancia y reparación de mutaciones es más eficaz en las secuencias genéticas que codifican para proteína.
Derechos: En la imagen, Núria López-Bigas con el equipo que ha contribuido al estudio publicado en Nature Genetics esta semana.
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La vigilancia y reparación de errores durante la replicación del ADN no es igual de intensa en todos los puntos del genoma humano. Científicos del Instituto de Investigación Biomédica (IRB Barcelona), liderados por la investigadora ICREA Núria López-Bigas, demuestran que el mecanismo de reparación del ADN es más eficaz en las regiones de los genes que contienen la información para producir proteínas.


Los genes tienen una estructura básica dividida en exones e intrones. En los exones reside la secuencia genética para sintetizar proteínas, mientras que en los intrones hay otro tipo de información menos relevante. Se sabe que los exones no varían demasiado según la especie, es decir, son similares entre humanos, ratones o gusanos, por ejemplo. La explicación científica aceptada es que los exones son regiones demasiado importantes para la viabilidad de los organismos y muchas mutaciones no están permitidas, ya que acostumbran a tener efectos dramáticos.



“La selección negativa seguro que es un factor clave de la conservación de los exones entre especies, pero ahora sabemos que no es el único. Demostramos por primera vez que los exones reciben menos mutaciones que otras regiones de los genes porque hay más reparación”, explica Núria López-Bigas, líder del laboratorio Genómica Biomédica.


Los investigadores analizaron tumores de colon en los cuales la polimerasa, la copiadora, tiene una mutación. Por esta razón, dichos tumores tienen muchas más mutaciones. Ahora bien, cuando compararon el número de mutaciones entre exones e intrones, observaron que en los exones había muchas menos de las esperables.


Entonces analizaron los genomas de un tipo de cáncer de cerebro infantil donde además de la mutación en la polimerasa —como en los tumores previamente analizados—, también está mutado el sistema de reparación. Observaron que en estos tumores, el número de mutaciones en los exones era tan alta como era de esperar.


“El mecanismo de reparación vigila que no se acumulen mutaciones en el genoma, y especialmente, en los exones”, constata Joan Frigola, estudiante de doctorado y primer autor del artículo junto con el investigador postdoctoral Sabarinathan Radhakrishnan.



Los investigadores dan una pista de cual podría ser el mecanismo por el cual la maquinaria de reparación en los exones es más eficiente que en los intrones. La respuesta, dicen, se encuentra en que los exones tienen un contenido muy alto de una marca específica, H3K36me3, que permite un reclutamiento más grande de proteínas de reparación hacia los exones, haciendo más eficaz la reparación.


“Nuestras maquinarias de reparación “saben” que tienen que fijarse en las regiones más importantes del genoma. Y este conocimiento hay que tenerlo en cuenta en el momento de estudiar los procesos de mutación y de reparación del ADN y en estudios sobre evolución, tanto de los tumores como de las especies”, concluye López-Bigas.


El laboratorio dirigido por López-Bigas inició este trabajo en la Universidad Pompeu Fabra y lo ha finalizado en el IRB Barcelona. El estudio ha contado con la financiación del Consejo Europeo de Investigación (ERC en inglés), el programa H2020 de la UE, el Ministerio de Economía y Competitividad/Fondos Feder y la Fundación La Marató de TV3.



Artículo de referencia: Joan Frigola, Radhakrishnan Sabarinathan, Loris Mularoni, Ferran Muiños, Abel Gonzalez-Perez & Núria López-Bigas Reduced mutation rate in exons due to differential mismatch repairNature Genetics (2017). Doi: 10.1038/ng.3991
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