2. Academic Validation
  3. Nuclear exosome targeting complex safeguards hematopoietic stem cell self-renewal and genomic integrity through resolving R loops

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

  • Cell Rep. 2025 Dec 23;44(12):116650. doi: 10.1016/j.celrep.2025.116650.
Yinghao Pan 1,  Hongna Zuo 1,  Xianjin Yan 1,  Jiali Li 1,  Yuwen Li 1,  Jin Li 1,  You Wu 2,  Liquan Hong 1,  Mingwei Wang 1,  Aiwei Wu 3,  Zhenyu Ju 4,  Yawei Gao 5,  Hu Wang 6
Affiliations

Affiliations

  • 1 Zhejiang Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, The Third People's Hospital of Deqing, Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou 311121, China.
  • 2 Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China.
  • 3 Zhejiang Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, The Third People's Hospital of Deqing, Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou 311121, China. Electronic address: [email protected].
  • 4 Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China. Electronic address: [email protected].
  • 5 Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China. Electronic address: [email protected].
  • 6 Zhejiang Key Laboratory of Medical Epigenetics, School of Basic Medical Sciences, The Third People's Hospital of Deqing, Department of Cardiology, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou 311121, China. Electronic address: [email protected].
PMID: 41353749 DOI: 10.1016/j.celrep.2025.116650
Abstract

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.

Keywords

CP: molecular biology; CP: stem cell research; DNA damage; NEXT complex; hematopoietic stem cells; lymphoma; self-renewal; transcription-coupled R loops.

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