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Peer-reviewedCC BY 4.0Molecular cell

5-azacytosine induces cytotoxicity via 5-methylcytosine depletion on chromatin-associated RNA in leukemia

  • Boyang Gao1,2,3,4
  • Ying Li5,4
  • Xinyuan Ma2,6,4
  • Long Zhao2,6
  • Zhongyu Zou2,6
  • Juyeong Hong5
  • Junhong Xiang2,6
  • Xiaoyang Dou2,6
  • Feng-Chun Yang7,8
  • Mingjiang Xu5,8
  • Chuan He2,6,7,9
9 affiliations
  1. 1Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL 60637, USA
  2. 2Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA
  3. 3Present address: Independent Research Groups, Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany
  4. 4These authors contributed equally
  5. 5Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
  6. 6Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA
  7. 7Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
  8. 8May’s Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
  9. 9Lead contact
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Abstract

SUMMARY: 5-azacytidine (5-azaC) is a DNA hypomethylating agent clinically used in myeloid malignancies. As a ribonucleoside analogue, 5-azaC incorporates more readily into nascent RNA than DNA. Here, we demonstrate that RNA 5-methylcytosine (m5C) depletion by 5-azaC treatment, particularly at early time points, is sufficient to induce leukemia cell death. In contrast to its DNA demethylation function, the RNA-dependent effects of 5-azaC lead to transcriptional repression, disrupting genes involved in cell-cycle regulation and DNA repair. Mechanistically, depletion of m5C by 5-azaC in chromatin-associated RNA (caRNA) disrupts the MBD6-mediated H2AK119ub deubiquitination. This also impairs SRSF2 recruitment and the downstream H3K27ac deposition by p300. Consistently, loss of the caRNA methyltransferase NSUN2 caused prolonged cell cycle, defective DNA repair, and shifted hematopoietic lineage commitment toward erythropoiesis, mirroring the effects of 5-azaC treatment. Our findings highlight the transcriptional repression by 5-azaC through depleting caRNA m5C, providing additional insights into the mechanism of action for 5-azaC.

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Cite

BibTeXRIS
BibTeX
@article{gao20265azacytosine,
  title = {{5-azacytosine induces cytotoxicity via 5-methylcytosine depletion on chromatin-associated RNA in leukemia}},
  author = {Boyang Gao and Ying Li and Xinyuan Ma and Long Zhao and Zhongyu Zou and Juyeong Hong and Junhong Xiang and Xiaoyang Dou and Feng-Chun Yang and Mingjiang Xu and Chuan He},
  journal = {Molecular cell},
  year = {2026},
  month = sep,
  doi = {10.1016/j.molcel.2026.08.018},
  url = {https://doi.org/10.1016/j.molcel.2026.08.018},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - 5-azacytosine induces cytotoxicity via 5-methylcytosine depletion on chromatin-associated RNA in leukemia
AU  - Boyang Gao
AU  - Ying Li
AU  - Xinyuan Ma
AU  - Long Zhao
AU  - Zhongyu Zou
AU  - Juyeong Hong
AU  - Junhong Xiang
AU  - Xiaoyang Dou
AU  - Feng-Chun Yang
AU  - Mingjiang Xu
AU  - Chuan He
PY  - 2026
DA  - 2026/09/15
JO  - Molecular cell
DO  - 10.1016/j.molcel.2026.08.018
UR  - https://doi.org/10.1016/j.molcel.2026.08.018
AB  - SUMMARY: 5-azacytidine (5-azaC) is a DNA hypomethylating agent clinically used in myeloid malignancies. As a ribonucleoside analogue, 5-azaC incorporates more readily into nascent RNA than DNA. Here, we demonstrate that RNA 5-methylcytosine (m5C) depletion by 5-azaC treatment, particularly at early time points, is sufficient to induce leukemia cell death. In contrast to its DNA demethylation function, the RNA-dependent effects of 5-azaC lead to transcriptional repression, disrupting genes involved in cell-cycle regulation and DNA repair. Mechanistically, depletion of m5C by 5-azaC in chromatin-associated RNA (caRNA) disrupts the MBD6-mediated H2AK119ub deubiquitination. This also impairs SRSF2 recruitment and the downstream H3K27ac deposition by p300. Consistently, loss of the caRNA methyltransferase NSUN2 caused prolonged cell cycle, defective DNA repair, and shifted hematopoietic lineage commitment toward erythropoiesis, mirroring the effects of 5-azaC treatment. Our findings highlight the transcriptional repression by 5-azaC through depleting caRNA m5C, providing additional insights into the mechanism of action for 5-azaC.
SN  - 1097-2765
SN  - 1097-4164
ER  -