# CNOT7 facilitates radiation resistance in colorectal cancer through TRIM21/XRCC6-mediated non-homologous end joining repair

## TL;DR

This study identifies CNOT7 as a key player in colorectal cancer radiotherapy resistance by enhancing DNA repair through the TRIM21/XRCC6 pathway.

## Contribution

The study reveals a novel mechanism by which CNOT7 promotes DNA repair and radiotherapy resistance in CRC through the TRIM21/XRCC6 axis.

## Key findings

- Elevated CNOT7 expression correlates with poor radiotherapy response and lower disease control rate in CRC patients.
- CNOT7 knockdown increases radiosensitivity by impairing DNA repair and promoting apoptosis in CRC models.
- Targeting the CNOT7-TRIM21-XRCC6 axis with STL127705 and radiotherapy suppresses tumor growth in CRC models.

## 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.