Artículo del mes
abril 2018

A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets

Referencia artículo:
J Exp Med. 2018 Mar 5;215(3):761-771.
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.
Resumen
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.
Sobre el grupo investigador