Predicting AID off-targets: A step forward

Abstract

In this issue of JEM, Álvarez-Prado et al. (https://doi.org/10.1084/jem.20171738) designed a DNA capture library allowing them to identify 275 genes targeted by AID in mouse germinal center B cells. Using the molecular features of these genes to feed a machine-learning algorithm, they determined that high-density RNA PolII and Spt5 binding-found in 2.3% of the genes-are the best predictors of AID specificity.

Insight from Claude-Agnès Reynaud and Jean-Claude Weill

The various outcomes of AID-mediated cytidine deamination are represented, from left to right, with the relative involvement of mutagenesis and DNA strand break for each of them. (1) Error-free repair, mobilizing either BER or MMR to faithfully restore genomic information after excision of the modified base (DNA incision is represented by a yellow star). (2) Ignorance of DNA damage, copied by replication (a configuration that is the sole outcome of cytidine deamination in Msh2xUng KO mice, doubly deficient for the MMR and BER pathways). (3) Error-prone lesion bypass of the abasic site generated by Ung-mediated uracil excision. (4) Error-prone repair generated by MMR-mediated recruitment of DNA polymerase eta (specific to Ig gene hypermutation process). Whereas error-prone repair predominates at the Ig loci, various degrees of error-free repair take place at AID off-targets, whose precise extent remains to be determined, notably in human B cells.