TY - JOUR
T1 - A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets
AU - Álvarez-Prado, Ángel F.
AU - Pérez-Durán, Pablo
AU - Pérez-García, Arantxa
AU - Benguria, Alberto
AU - Torroja, Carlos
AU - de Yébenes, Virginia G.
AU - Ramiro, Almudena R.
N1 - Publisher Copyright:
© 2018 álvarez-Prado et al.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85042859325&partnerID=8YFLogxK
U2 - 10.1084/jem.20171738
DO - 10.1084/jem.20171738
M3 - Article
C2 - 29374026
AN - SCOPUS:85042859325
SN - 0022-1007
VL - 215
SP - 761
EP - 771
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 3
ER -