2. Academic Validation
  3. A CRISPR-Cas9 screen reveals genetic determinants of the cellular response to decitabine

A CRISPR-Cas9 screen reveals genetic determinants of the cellular response to decitabine

  • EMBO Rep. 2025 Feb 10. doi: 10.1038/s44319-025-00385-w.
Pinqi Zhang # 1 2,  Zhuqiang Zhang # 1,  Yiyi Wang 1 2,  Wenlong Du 1,  Xingrui Song 3,  Weiyi Lai 3,  Hailin Wang 3,  Bing Zhu 4 5 6,  Jun Xiong 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 2 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 The State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, 100085, China.
  • 4 State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. zhubing@ibp.ac.cn.
  • 5 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. zhubing@ibp.ac.cn.
  • 6 New Cornerstone Science Laboratory, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. zhubing@ibp.ac.cn.
  • 7 State Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. xiongjun@ibp.ac.cn.
  • # Contributed equally.
PMID: 39930152 DOI: 10.1038/s44319-025-00385-w
Abstract

Decitabine (DAC), a well-recognized DNA hypomethylating agent, has been applied to treat acute myeloid leukemia. However, clinic investigations revealed that DNA methylation reduction does not correlate with a clinical response, and relapse is prevalent. To gain a better understanding of its anti-tumor mechanism, we perform a temporally resolved CRISPR-Cas9 screen to identify factors governing the DAC response. We show that DNA damage generated by DNMT-DNA adducts and 5-aza-dUTP misincorporation through the dCMP deaminase DCTD act as drivers of DAC-induced acute cytotoxicity. The DNA damage that arises during the next S phase is dependent on DNA replication, unveiling a trans-cell cycle effect of DAC on genome stability. By exploring candidates for synthetic lethality, we unexpectedly uncover that KDM1A promotes survival after DAC treatment through interactions with ZMYM3 and CoREST, independent of its demethylase activity or regulation of viral mimicry. These findings emphasize the importance of DNA repair pathways in DAC response and provide potential biomarkers.

Keywords

DCTD; DNA Damage; DNA Methylation; Decitabine; KDM1A.

Figures
Products