2. Academic Validation
  3. LncRNA CTBP1-DT-encoded microprotein DDUP sustains DNA damage response signalling to trigger dual DNA repair mechanisms

LncRNA CTBP1-DT-encoded microprotein DDUP sustains DNA damage response signalling to trigger dual DNA repair mechanisms

  • Nucleic Acids Res. 2022 Aug 12;50(14):8060-8079. doi: 10.1093/nar/gkac611.
Ruyuan Yu 1 2,  Yameng Hu 1 2,  Shuxia Zhang 1 2,  Xincheng Li 1 2,  Miaoling Tang 1 2,  Meisongzhu Yang 1 2,  Xingui Wu 1 2,  Ziwen Li 1 2,  Xinyi Liao 1 2,  Yingru Xu 1 2,  Man Li 1 2,  Suwen Chen 1 2,  Wanying Qian 1 2,  Li-Yun Gong 3,  Libing Song 4,  Jun Li 1 2
Affiliations

Affiliations

  • 1 Program of Cancer Research, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, China.
  • 2 Department of Biochemistry, Zhongshan school of medicine, Sun Yat-sen University, China.
  • 3 Guangdong Provincial Key Laboratory for Genome Stability and Disease Prevention, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Health Science Center, Shenzhen University, China.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, China.
PMID: 35849344 DOI: 10.1093/nar/gkac611
Abstract

Sustaining DNA damage response (DDR) signalling via retention of DDR factors at damaged sites is important for transmitting damage-sensing and repair signals. Herein, we found that DNA damage provoked the association of ribosomes with IRES region in lncRNA CTBP1-DT, which overcame the negative effect of upstream open reading frames (uORFs), and elicited the novel microprotein DNA damage-upregulated protein (DDUP) translation via a cap-independent translation mechanism. Activated ATR kinase-mediated phosphorylation of DDUP induced a drastic 'dense-to-loose' conformational change, which sustained the RAD18/RAD51C and RAD18/PCNA complex at damaged sites and initiated RAD51C-mediated homologous recombination and PCNA-mediated post-replication repair mechanisms. Importantly, treatment with ATR Inhibitor abolished the effect of DDUP on chromatin retention of RAD51C and PCNA, thereby leading to hypersensitivity of Cancer cells to DNA-damaging chemotherapeutics. Taken together, our results uncover a plausible mechanism underlying the DDR sustaining and might represent an attractive therapeutic strategy in improvement of DNA damage-based Anticancer therapies.

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