Nuclear exosome targeting complex safeguards hematopoietic stem cell self-renewal and genomic integrity through resolving R loops

Pervasive transcription of the mammalian genome produces a vast repertoire of non-functional nascent transcripts, generating R loops and R-loop-induced DNA breaks. Such a coupling between continual transcription and a burst of R-loop formation, however, presents a challenge for hematopoietic stem cells (HSCs) to maintain their genome integrity. Here, we show that the nuclear exosome targeting (NEXT) complex, an RNA adaptor that targets non-functional nascent transcripts to the RNA exosome for decay, plays a pivotal role in overcoming this challenge. Hematopoietic-specific deletion of ZCCHC8, a core subunit of NEXT, not only leads to impaired HSC self-renewal but also causes elevated DNA lesions and upregulated DNA repair pathways in HSCs due to accumulated R loops. Moreover, dysregulation of ZCCHC8 occurs frequently in diffuse large B cell lymphoma (DLBCL) and is associated with poor clinical outcomes. Collectively, our findings highlight NEXT as a novel protector of HSCs and position it as a potential therapeutic target for DLBCL.