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

IF 6.2 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2025-03-01 Epub Date: 2025-02-10 DOI:10.1038/s44319-025-00385-w

Pinqi Zhang, Zhuqiang Zhang, Yiyi Wang, Wenlong Du, Xingrui Song, Weiyi Lai, Hailin Wang, Bing Zhu, Jun Xiong

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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.

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CRISPR-Cas9筛选揭示了细胞对地西他滨反应的遗传决定因素。

地西他滨（Decitabine， DAC）是一种公认的DNA低甲基化药物，已被用于治疗急性髓系白血病。然而，临床调查显示，DNA甲基化减少与临床反应无关，复发是普遍的。为了更好地了解其抗肿瘤机制，我们进行了暂时解析的CRISPR-Cas9筛选，以确定控制DAC反应的因素。我们发现DNMT-DNA加合物和5-aza-dUTP通过dCMP脱氨酶DCTD错掺入产生的DNA损伤是dac诱导的急性细胞毒性的驱动因素。在下一个S期出现的DNA损伤依赖于DNA复制，揭示了DAC对基因组稳定性的跨细胞周期效应。通过探索候选的合成致死性，我们意外地发现KDM1A通过与ZMYM3和CoREST的相互作用促进DAC治疗后的生存，而不依赖于其去甲基化酶活性或对病毒模仿的调节。这些发现强调了DNA修复途径在DAC反应中的重要性，并提供了潜在的生物标志物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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GSK3484862

来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.