HSPA1A and DNAJB1 regulate NELF condensate dynamics to safeguard transcriptional recovery under heat stress

  • Mol Cell. 2026 Feb 19;86(4):674-692.e10. doi: 10.1016/j.molcel.2026.01.015.
Shuyao Jiang  1 ,  Zixuan Jia  1 ,  Wenxuan Zhu  1 ,  Yu Liu  2 ,  Huanyi Fu  2 ,  Feifeng Zhu  3 ,  Zhuo Li  2 ,  Jiaye Yang  2 ,  Yiying Zhu  2 ,  Zhongxing Sun  2 ,  Tianyi Zhu  2 ,  Xuebo Quan  4 ,  Huipeng Jiao  2 ,  Kai Huang  4 ,  Zhibing Wu  5 ,  Wei Zou  6 ,  Bing Yang  2 ,  Yi Lu  7 ,  Long Zhang  2 ,  Fangfang Zhou  8 ,  Dong Fang  2 ,  Huasong Lu  9
Affiliations
  • 1. Department of Neurology of the Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • 2. Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • 3. Department of Neurology of the Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • 4. Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen 518132, China.
  • 5. Department of Radiation Oncology, Zhejiang Hospital, Hangzhou 310058, China.
  • 6. Insititute of Translational Medicine, Zhejiang University, Hangzhou 310058, China.
  • 7. Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200331, China.
  • 8. Institutes of Biology and Medical Sciences, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou 215000, China.
  • 9. Department of Neurology of the Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
PMID: 41653920 DOI: 10.1016/j.molcel.2026.01.015
Abstract

Promoter-proximal pausing by negative elongation factor (NELF) establishes a critical checkpoint for RNA polymerase II (RNA Pol II) transcription. Heat shock (HS) induces NELF to form nuclear condensates, yet how their dynamics are regulated and coupled to transcriptional adaptation remains unclear. Using a nanobody-based proximity labeling strategy (NbPro), we identify the molecular chaperones HSPA1A and DNAJB1 as key regulators of NELF condensate dynamics. Although dispensable for initial HS-induced transcriptional repression, chaperone-mediated regulation is required for efficient transcriptional reactivation during recovery. Mechanistically, DNAJB1 recognizes NELFA's tentacle domain and facilitates HSPA1A recruitment, thereby preventing aberrant aggregation and enabling timely condensate disassembly. Disruption of NELF condensate dynamics leads to persistent NELFA phosphorylation, impaired chromatin association, destabilized RNA Pol II pausing, and premature release of non-productive RNA Pol II complexes. Together, these findings reveal a chaperone-dependent mechanism that governs NELF condensate dynamics and highlight promoter-proximal pausing as a checkpoint to prevent immature RNA Pol II escape, rather than merely a means of transcriptional repression.

Keywords
NELF; RNA Pol II pausing; biomolecular condensate; heat shock.
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