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Chromatin-associated circRNA ciCRLF3(2) regulates cell differentiation blockage via activating non-homologous end joining–based DNA repair

Cell Death & Differentiation (2025)Cite this article

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Abstract

DNA damage response (DDR) is a complicated network that responds to DNA lesions to prevent their accumulation; a defective DDR is one hallmark of cancer. Although targeting DDR pathways has been considered as a therapeutic approach, DDR inhibitors have also been reported ineffective for treating some low mutation burden cancers, such as Mixed-lineage leukemia (MLL)-rearranged (MLL-r) leukemia, a clinically fatal and refractory malignancy. Exploring the roles and mechanisms of DDR pathways in these low mutation burden cancers may help understand the chromatin biology and develop therapeutic strategies. Here, we identified a set of DDR-related chromatin-associated circular RNAs (cacircRNAs) that regulate DNA repair via the non-homologous end joining (NHEJ) pathway, which is vital for meeting the high DNA repair demands during the progression of MLL-r leukemia. Among these cacircRNAs, we identified ciCRLF3(2) as a previously unknown component of the NHEJ complex. We showed that ciCRLF3(2) recruits NHEJ regulators to DNA lesions, supporting abundant DNA repair in leukemia cells. ciCRLF3(2) abundance is abnormally upregulated in MLL-r leukemia and indicates a poor prognosis. Targeting ciCRLF3(2) suppressed NHEJ-mediated DNA repair, leading to DNA damage and broad anti-cancer effects in vitro and in vivo. A patient-derived xenograft model of MLL-r leukemia further indicated that ciCRLF3(2) depletion can decrease the leukemic burden. These findings demonstrate the function of cacircRNAs in DDR and chromatin biology and reveal a new avenue for developing strategies to treat low mutation burden cancers, such as MLL-r leukemia.

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Fig. 1: High-throughput sequencing profiles cacircRNAs and identifies the redistribution of them in response to DNA damage.
Fig. 2: CacircRNAs downregulation improves DNA damage level and suppresses the progression of MLL-r leukemia.
Fig. 3: ciCRLF3(2) regulates DNA repair by NHEJ in MLL-r leukemia cells.
Fig. 4: NF90 binds to ciCRLF3(2) to regulates DNA repair by NHEJ in MLL-r leukemia cells.
Fig. 5: ciCRLF3(2) recruits NHEJ regulators.
Fig. 6: CacircRNAs silencing impairs the progression and infiltration of MLL-r leukemia in vivo.
Fig. 7: The potential value of ciCRLF3(2) in MLL-r leukemia.

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Data availability

The circRNA RNA-seq data in this study has been uploaded to Sequence Read Archive (SRA) database. The BioProject No. is PRJNA1276304. All other study data are included in the article and/or Supplemental Information. Any information required to reanalyze the data reported in this study is available from the corresponding authors (wangwt8@mail.sysu.edu.cn) upon request.

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Funding

This research was supported by National Key R&D Program of China (Nos.2021YFA1300502 and 2022YFA1303302), National Natural Science Foundation of China (Nos. 32170570,32370594, and 32400439), and Guangdong Province (Nos. 2021B1515020002 and 2022A1515140018), and Guangzhou (No. 2024A04J5004).

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  1. These authors contributed equally: Ke-Jia Pu, Xiao-Tong Chen, Shun-Xin Zhu.

Authors and Affiliations

  1. MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China

    Ke-Jia Pu, Xiao-Tong Chen, Shun-Xin Zhu, Yan An, Xin‑Yi Feng, Heng-Jing Huang, Cheng-Lin Zhou, Mei-Ying Ye, Yun-Chun Wei, Yi-Xuan Ma, Chen Fang, Nan Zhang, Bin-Rong Han, Jun-Yi Lian, Tian-Qi Chen, Yu-Meng Sun, Yue-Qin Chen & Wen-Tao Wang

  2. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, China

    Dan Wang

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Contributions

K.J.P., X.T.C. and S.X.Z. designed and performed the research, analyzed the data, and wrote the manuscript. Y.A., X.Y.F., J.Y.L., H.J.H., C.L.Z., M.Y.Y., B.R.H., Y.C.W., Y.X.M., C. F., N. Z., D. W., T.Q.C. and Y.M.S. performed the research and analyzed the data. K.J.P., X.T.C. and S.X.Z. collected and analyzed the clinical data. Y.Q.C. and W.T.W. designed the research, analyzed the data, and wrote the manuscript. The authors read and approved the final manuscript.

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Correspondence to Yue-Qin Chen or Wen-Tao Wang.

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All patient samples were obtained with informed consent from the first Affiliated Hospital of Sun Yat-sen University. Sample collection was approved by the Hospital’s Protection of Human Subjects Committee. Additionally, all animal experiments were approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University (Approval No. SYSU-IACUC-2023-B0438) and were performed in accordance with the approved protocols.

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Pu, KJ., Chen, XT., Zhu, SX. et al. Chromatin-associated circRNA ciCRLF3(2) regulates cell differentiation blockage via activating non-homologous end joining–based DNA repair. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01574-9

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