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hnRNPA2B1 deacetylation by SIRT6 restrains local transcription and safeguards genome stability

Cell Death & Differentiation volume 32, pages 382–396 (2025)Cite this article

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Abstract

Repair of double strand breaks (DSBs) by RNA-binding proteins (RBPs) is vital for ensuring genome integrity. DSB repair is accompanied by local transcriptional repression in the vicinity of transcriptionally active genes, but the mechanism by which RBPs regulate transcriptional regulation is unclear. Here, we demonstrated that RBP hnRNPA2B1 functions as a RNA polymerase-associated factor that stabilizes the transcription complex under physiological conditions. Following a DSB, hnRNPA2B1 is released from damaged chromatin, reducing the efficiency of RNAPII complex assembly, leading to local transcriptional repression. Mechanistically, SIRT6 deacetylates hnRNPA2B1 at K113/173 residues, enforcing its rapid detachment from DSBs. This process disrupts the integrity of the RNAPII complex on active chromatin, which is a pre-requisite for transient but complete repression of local transcription. Functionally, the overexpression of an acetylation mimic stabilizes the transcription complex and facilitates the functioning of the transcription machinery. hnRNPA2B1 acetylation status was negatively correlated with SIRT6 expression, and acetylation mimic enhanced radio-sensitivity in vivo. Our findings demonstrate that hnRNPA2B1 is crucial for transcriptional repression. We have uncovered the missing link between DSB repair and transcriptional regulation in genome stability maintenance, highlighting the potential of hnRNPA2B1 as a therapeutic target.

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Fig. 1: Identification of hnRNPA2B1 as a potential transcriptional regulator of the DNA damage response.
Fig. 2: hnRNPA2B1 disassociates from RNA polymerase II complex and disrupts its integrity in response to DNA damage.
Fig. 3: Chromatin hnRNPA2B1 is deacetylated and released from DSB sites in response to DNA damage.
Fig. 4: SIRT6 interacts with, and deacetylates hnRNPA2B1 in response to DNA damage.
Fig. 5: hnRNPA2B1 deacetylation at K113/173 residues by SIRT6 is a pre-requisite for its chromatin dissociation.
Fig. 6: Deacetylation of hnRNPA2B1 by SIRT6 disrupts the integrity of the RNA polymerase II complex and suppresses transcriptional activity at DSB sites.
Fig. 7: Deacetylation of hnRNPA2B1 is beneficial for maintaining genome stability.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China [32090030, 32090033, 82430096, 82472781 and 82002986]; the Guangdong Basic and Applied Basic Research Foundation (2021A1515011126); the Shenzhen Municipal Commission of Science and Technology Innovation [JCYJ20220818100015032, JCYJ20220818100016034, RCYX20210706092040047]; the Shenzhen Medical Research Fund [A2303025 and B2302010]; the Shenzhen University 2035 Program for Excellent Research and Shenzhen University Startup Grant for Youth, and the Program for Youzuzhikeyan of Shenzhen University. The authors would like to thank Dr Roger Greenberg (University of Pennsylvania, USA) for providing the U2OS-DSB reporter cells, and Dr Jessica Tamanini of ETediting, UK for English language editing prior to submission.

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  1. These authors contributed equally: Feng Chen, Wenchao Xu, Ming Tang.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, International Cancer Center, Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, Marshall Laboratory of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China

    Feng Chen, Wenchao Xu, Yuan Tian, Yuxin Shu, Xingkai He, Linmin Zhou, Qi Liu, Qian Zhu, Xiaopeng Lu, Jun Zhang & Wei-Guo Zhu

  2. Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China

    Ming Tang

  3. School of Basic Medical Sciences, Wannan Medical College, Wuhu, Anhui, China

    Yuxin Shu & Wei-Guo Zhu

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Contributions

JZ and WGZ contributed to the design of the research, conceived the study, guided the research and revised the manuscript; FC, WCX, and JZ wrote the manuscript; FC, WCX, MT, YXS, and JZ performed the experimental study and analyzed data; XKH and QL helped the mice maintenance; MT provided the clinical tissue samples; LMZ analyzed the clinical samples; YT, QZ, and XPL discussed the study and provided suggestions.

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Correspondence to Jun Zhang or Wei-Guo Zhu.

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All methods were performed in accordance with the relevant guidelines and regulations. Studies using human specimens were approved by the Clinical Research Ethics Committee of Shenzhen University. The patients provided written informed consent to the use of their resected tissues for research purposes. All mouse experiments were approved by Shenzhen University Animal Care and Use Committee and were conducted in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.

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Chen, F., Xu, W., Tang, M. et al. hnRNPA2B1 deacetylation by SIRT6 restrains local transcription and safeguards genome stability. Cell Death Differ 32, 382–396 (2025). https://doi.org/10.1038/s41418-024-01412-4

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