A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets
| Autor: | Alberto Benguria, Ángel F. Álvarez-Prado, Carlos Torroja, Pablo Pérez-Durán, Almudena R. Ramiro, Arantxa Pérez-García, Virginia G. de Yébenes |
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| Přispěvatelé: | Ministerio de Educación, Cultura y Deporte (España), Ministerio de Economía, Industria y Competitividad (España), European Commission, European Regional Development Fund, European Research Council, Fundación ProCNIC |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Genome instability IG GENES Immunology Somatic hypermutation Computational biology Genome DEFICIENT MICE Mice 03 medical and health sciences 0302 clinical medicine Activation-induced (cytidine) deaminase C-MYC Animals Immunology and Allergy INDUCED CYTIDINE DEAMINASE SEQUENCING REVEALS Gene Research Articles biology Brief Definitive Report Germinal center DNA BREAKS Base excision repair Germinal Center SUPER-ENHANCERS 030104 developmental biology B-CELL LYMPHOMAS biology.protein DNA mismatch repair 030215 immunology CLASS SWITCH RECOMBINATION GENOMIC INSTABILITY |
| Zdroj: | Repisalud Instituto de Salud Carlos III (ISCIII) The Journal of Experimental Medicine |
| ISSN: | 0022-1007 |
| Popis: | Álvarez-Prado et al. report a detailed map of AID-induced off-target mutations and identify molecular features that predict gene mutability. They identify a novel AID hotspot and demonstrate that base excision and mismatch repair back up each other to repair most AID deamination events. 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. |
| Databáze: | OpenAIRE |
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