Nbs1 ChIP-Seq Identifies Off-Target DNA Double-Strand Breaks Induced by AID in Activated Splenic B Cells

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Activation-induced cytidine deaminase (AID) is required for diversifying antibodies during immune responses, and it does this by introducing mutations and DNA breaks into antibody genes. How AID is targeted is not understood, and it induces chromosomal translocations, mutations, and double-strand breaks (DSBs) at sites other than antibody genes in activated B cells. To determine what makes an off-target DNA site a target for AID-induced DSBs, we identify and characterize hundreds of genome-wide DSBs induced by AID during B cell activation. Interestingly, many of the DSBs are within or adjacent to two types of tandemly repeated simple sequences, which have characteristics that might explain why they are targeted. We find that most of the DSBs are two-ended, consistent with their generation during G1 phase of the cell cycle, which is when AID induces DNA breaks in antibody genes. However, a minority is one-ended, consistent with replication encountering an AID-induced single-strand break, thereby creating a DSB. Both types of off-target DSBs, but especially those present during S phase of the cell cycle, lead to chromosomal translocations, deletions and gene amplifications that can promote B cell lymphomagenesis.

Vyšlo v časopise: Nbs1 ChIP-Seq Identifies Off-Target DNA Double-Strand Breaks Induced by AID in Activated Splenic B Cells. PLoS Genet 11(8): e32767. doi:10.1371/journal.pgen.1005438
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005438

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