Noncoding RNA transcription targets AID to divergently transcribed loci in B cells

The 11-subunit RNA exosome is thought to regulate the mammalian noncoding transcriptome; here, a mouse model is generated in which the essential Exosc3 subunit of the RNA exosome in B cells is conditionally deleted, revealing a link between sites of genomic RNA exosome function and AID-mediated chromosomal translocations. Noncoding RNAs pinpoint AID in B cells It is difficult to identify rare non-coding RNA (ncRNA) species because of their low abundance in cells and the fact that they are rapidly degraded, mainly through the action of the cellular non-coding RNA 3′–5′ degradation complex, RNA exosome. Uttiya Basu and colleagues have generated a mouse model in which an essential subunit (exosome component 3, Exosc3 ) of the RNA exosome can be conditionally inactivated in B cells. Exosc3-deficient B cells lack the recombination and mutagenesis activities that are necessary for generating antibodies. Many non-coding RNAs normally degraded are found in these cells, including xTSS-RNAs, a type of antisense RNA encoded at transcription start sites. Surprisingly, the locations of the xTSS-RNAs correlate with sites of translocation breakages. The model suggested is that antisense transcription of the ncRNAs recruits activation-induced cytidine deaminase (AID) and results in formation of single-strand DNA; pairing with the RNAs makes R-loops that can lead to genomic instability. The vast majority of the mammalian genome has the potential to express noncoding RNA (ncRNA). The 11-subunit RNA exosome complex is the main source of cellular 3′–5′ exoribonucleolytic activity and potentially regulates the mammalian noncoding transcriptome 1 . Here we generated a mouse model in which the essential subunit Exosc3 of the RNA exosome complex can be conditionally deleted. Exosc3 -deficient B cells lack the ability to undergo normal levels of class switch recombination and somatic hypermutation, two mutagenic DNA processes used to generate antibody diversity via the B-cell mutator protein activation-induced cytidine deaminase (AID) 2 , 3 . The transcriptome of Exosc3 -deficient B cells has revealed the presence of many novel RNA exosome substrate ncRNAs. RNA exosome substrate RNAs include xTSS-RNAs, transcription start site (TSS)-associated antisense transcripts that can exceed 500 base pairs in length and are transcribed divergently from cognate coding gene transcripts. xTSS-RNAs are most strongly expressed at genes that accumulate AID-mediated somatic mutations and/or are fre