Reference

J Exp Med. 2018 Mar 5;215(3):761-771. doi: 10.1084/jem.20171738 portadaJEM

Authors

Álvarez-Prado, Á.F., Pérez-Durán, P., Pérez-García, A., Benguria, A., Torroja, C., Yébenes, V.G. de, Ramiro, A.R.

Abstract

Activation-induced deaminase (AID) initiates antibody diversification in germinal center (GC) B cells through the deamination of cytosines on immunoglobulin genes. AID can also target other regions in the genome, triggering mutations or chromosome translocations, with major implications for oncogenic transformation. However, understanding the specificity of AID has proved extremely challenging. We have sequenced at very high depth >1,500 genomic regions from GC B cells and identified 275 genes targeted by AID, including 30 of the previously known 35 AID targets. We have also identified the most highly mutated hotspot for AID activity described to date. Furthermore, integrative analysis of the molecular features of mutated genes coupled to machine learning has produced a powerful predictive tool for AID targets. We also have found that base excision repair and mismatch repair back up each other to faithfully repair AID-induced lesions. Finally, our data establish a novel link between AID mutagenic activity and lymphomagenesis.

 

Description

En este trabajo hemos analizado el daño al que está sometido el genoma de los linfocitos B durante la respuesta inmune debido a la actividad de AID. Gracias a una nueva metodología basada en secuenciación masiva hemos identificado y caracterizado la mayor colección de dianas mutacionales de AID publicada hasta la fecha. Además, hemos desarrollado un modelo de machine learning capaz de predecir nuevas dianas de esta enzima. En conjunto, nuestro estudio ha permitido mejorar la comprensión de los mecanismos que rigen la actividad mutagénica de AID y su contribución al desarrollo de linfoma.

 

 

foto grupo julio18

 

REFERENCIA DEL GRUPO INVESTIGADOR

El laboratorio de Biología de linfocitos B del Centro Nacional de Investigaciones Cardiovasculares investiga varios aspectos de la fisiología de las células B, con un especial interés en los mecanismos reguladores y de diversificación que tienen lugar en los centros germinales durante la respuesta inmune. Además, estamos interesados en comprender cuál es el papel de los linfocitos B en el al desarrollo de patologías de alta incidencia en humanos, como el linfoma o la aterosclerosis.

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