TRIM26-Mediated Ubiquitination and Degradation of DDRGK1 Suppress NSCLC Progression by Inhibiting DNA Repair and Promoting Apoptosis
- 1Zhejiang Key Laboratory of Medical Epigenetics, Key Laboratory of Aging and Cancer Biology of Zhejiang Province, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou 311121, China
Abstract
The high incidence and poor prognosis of non-small-cell lung cancer (NSCLC) underscore the urgent need to elucidate the molecular mechanisms underlying its progression and chemoresistance. Here, we investigated the role of DDRGK domain-containing protein 1 (DDRGK1) in NSCLC and identified a novel regulatory axis governing its protein stability. Clinically, DDRGK1 was markedly upregulated in NSCLC tissues, and elevated DDRGK1 expression correlated with advanced tumor stage, poor overall survival, and chemoresistance. Functionally, DDRGK1 knockout significantly suppressed NSCLC cell growth, an effect reversed by DDRGK1 re-expression. Mechanistically, tripartite motif-containing protein 26 (TRIM26) was identified as the E3 ubiquitin ligase that catalyzed K48-linked polyubiquitination of DDRGK1 at K267, promoting its degradation. This modification antagonized E3 UFM1-protein ligase 1 (UFL1)-mediated UFMylation at the same residue, thereby fine-tuning DDRGK1 stability. Functional enrichment analysis showed that DDRGK1-interacting proteins and proteins differentially expressed in DDRGK1-knockout cells were predominantly associated with the DNA damage response and apoptosis. Consistently, DDRGK1 knockout suppressed ATR phosphorylation and augmented cisplatin-induced apoptosis in NSCLC cells. Collectively, these findings define the regulatory mechanism of DDRGK1, establish it as a key regulator of NSCLC progression, and highlight its potential as a therapeutic target for overcoming chemoresistance.
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BibTeX
@article{guo2026trim26mediated,
title = {{TRIM26-Mediated Ubiquitination and Degradation of DDRGK1 Suppress NSCLC Progression by Inhibiting DNA Repair and Promoting Apoptosis}},
author = {Yanmin Guo and Qifan Guo and Jingjin Yu and Yu Cao and Dexin Rao and Ziruo Guo and Binglong Li and Fanjian Jia and Qian Liang and Yang Zhuang and Shiwen Xu and Yaxiang Wang and Miao Wang and Yusheng Cong},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms272110014},
url = {https://www.mdpi.com/1422-0067/27/21/10014},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - TRIM26-Mediated Ubiquitination and Degradation of DDRGK1 Suppress NSCLC Progression by Inhibiting DNA Repair and Promoting Apoptosis
AU - Yanmin Guo
AU - Qifan Guo
AU - Jingjin Yu
AU - Yu Cao
AU - Dexin Rao
AU - Ziruo Guo
AU - Binglong Li
AU - Fanjian Jia
AU - Qian Liang
AU - Yang Zhuang
AU - Shiwen Xu
AU - Yaxiang Wang
AU - Miao Wang
AU - Yusheng Cong
PY - 2026
DA - 2026/11/08
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms272110014
UR - https://www.mdpi.com/1422-0067/27/21/10014
AB - The high incidence and poor prognosis of non-small-cell lung cancer (NSCLC) underscore the urgent need to elucidate the molecular mechanisms underlying its progression and chemoresistance. Here, we investigated the role of DDRGK domain-containing protein 1 (DDRGK1) in NSCLC and identified a novel regulatory axis governing its protein stability. Clinically, DDRGK1 was markedly upregulated in NSCLC tissues, and elevated DDRGK1 expression correlated with advanced tumor stage, poor overall survival, and chemoresistance. Functionally, DDRGK1 knockout significantly suppressed NSCLC cell growth, an effect reversed by DDRGK1 re-expression. Mechanistically, tripartite motif-containing protein 26 (TRIM26) was identified as the E3 ubiquitin ligase that catalyzed K48-linked polyubiquitination of DDRGK1 at K267, promoting its degradation. This modification antagonized E3 UFM1-protein ligase 1 (UFL1)-mediated UFMylation at the same residue, thereby fine-tuning DDRGK1 stability. Functional enrichment analysis showed that DDRGK1-interacting proteins and proteins differentially expressed in DDRGK1-knockout cells were predominantly associated with the DNA damage response and apoptosis. Consistently, DDRGK1 knockout suppressed ATR phosphorylation and augmented cisplatin-induced apoptosis in NSCLC cells. Collectively, these findings define the regulatory mechanism of DDRGK1, establish it as a key regulator of NSCLC progression, and highlight its potential as a therapeutic target for overcoming chemoresistance.
SN - 1422-0067
ER -