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
  • 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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