ArticleCell death & disease2025
CNOT7 facilitates radiation resistance in colorectal cancer through TRIM21/XRCC6-mediated non-homologous end joining repair.
Article in Cell death & disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.Translational oncology · 2026Review
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12 authors.
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Abstract
Radiotherapy is essential in the treatment of colorectal cancer (CRC), but the presence of drug resistance leads to poor prognosis for CRC patients. Identifying targets and mechanisms for regulating radiotherapy resistance has high clinical value. This study identifies CCR4-NOT transcription complex subunit 7 (CNOT7) as a key factor mediating radiotherapy resistance in CRC by stabilizing XRCC6 protein and enhancing non-homologous end joining (NHEJ) mediated DNA damage repair (DDR) pathway. Proteomic analysis of 45 CRC tissues revealed that elevated CNOT7 expression correlates with poorer responses to neoadjuvant radiotherapy and lower disease control rate (DCR). We demonstrated that CNOT7 knockdown enhances radiosensitivity by impairing NHEJ mediated double-strand breaks (DSBs) repair and promoting apoptosis in vitro and in vivo. Mechanistically, CNOT7 interacts with XRCC6 to stabilize its protein levels by inhibiting TRIM21-mediated K48-linked ubiquitination at lysine 526, thereby facilitating efficient DNA repair. CNOT7 accelerates degradation of TRIM21 mRNA through its deadenylase activity. Additionally, the combination of STL127705, an inhibitor of the XRCC6/XRCC5 heterodimer, with radiotherapy notably suppressed tumor growth in patient-derived xenograft (PDX) and cell line mouse transplant tumor models, especially in the context of CNOT7 deficiency. These findings elucidate the function of CNOT7 in promoting DNA repair and radiotherapy resistance in CRC, highlighting that targeting the CNOT7-TRIM21-XRCC6 axis provides a promising therapeutic approach to overcome radiotherapy resistance and improve clinical outcomes for CRC patients.
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