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Background <p>DDA1 <!--Query ID="Q1" Text="Please check article title if captured and presented correctly. Otherwise, amend if necessary. " Resolved="yes"-->is a protein involved in protein degradation, cell cycle regulation, and DNA damage repair. Although its expression varies across tumor types, the precise role of DDA1 in gliomagenesis remains unclear.</p> Methods <p>We<!--Query ID="Q2" Text="Please confirm if the author names are presented accurately. " Resolved="yes"--> investigated the function of DDA1 in multiple glioblastoma cell models using biochemical assays, phosphorylation analysis, subcellular localization studies, and integrated genomic and transcriptomic profiling to determine its signaling interactions and downstream effects.</p> Results <p>We i<!--Query ID="Q3" Text="Please check if affiliations were captured and presented correctly. Otherwise, kindly amend if necessary. " Resolved="yes"-->dentified a physical association between cytoplasmic DDA1 and Raptor, a core component of lysosome-associated mTORC1. Amino acid stimulation triggered phosphorylation of DDA1 at serine 33 promoting its nuclear translocation and involvement in DNA damage repair. Integrated transcriptomic analyses revealed that the mTORC1-DDA1<sup>S33</sup>-DNA repair axis regulates the expression of a subset of metabolic genes, including ENO2, CA12, and NMRK1. Functional assays further suggested that these genes contribute to the survival capacity of glioblastoma cells, particularly under DDA1-deficient conditions. Consistently, DDA1 deficiency markedly impaired glioblastoma growth and induced compensatory upregulation of metabolic activity.</p> Conclusion <p>Our findings identify DDA1 as a previously unrecognized phosphorylation target downstream of mTORC1 and a critical mediator of the mTORC1 driven DNA damage response. Through its involvement in DNA repair and metabolic gene regulation, DDA1 appears to support glioblastoma progression, providing mechanistic insight into mTORC1 related gliomagenesis and suggesting potential therapeutic relevance.</p>

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Amino-acids-mTORC1-driven DDA1 phosphorylation promotes DNA repair and glioblastoma progression

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月25日

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  • Xing Chen,
  • Zhixing Wang,
  • An Yan,
  • Yunpeng Liu,
  • Ruimin Zhu,
  • Li Li,
  • Doudou Xu,
  • Ruixue Liu,
  • Xiangwen Zhan,
  • Bin Yin,
  • Wei Han,
  • Xiaozhong Peng

摘要

Background

DDA1 is a protein involved in protein degradation, cell cycle regulation, and DNA damage repair. Although its expression varies across tumor types, the precise role of DDA1 in gliomagenesis remains unclear.

Methods

We investigated the function of DDA1 in multiple glioblastoma cell models using biochemical assays, phosphorylation analysis, subcellular localization studies, and integrated genomic and transcriptomic profiling to determine its signaling interactions and downstream effects.

Results

We identified a physical association between cytoplasmic DDA1 and Raptor, a core component of lysosome-associated mTORC1. Amino acid stimulation triggered phosphorylation of DDA1 at serine 33 promoting its nuclear translocation and involvement in DNA damage repair. Integrated transcriptomic analyses revealed that the mTORC1-DDA1S33-DNA repair axis regulates the expression of a subset of metabolic genes, including ENO2, CA12, and NMRK1. Functional assays further suggested that these genes contribute to the survival capacity of glioblastoma cells, particularly under DDA1-deficient conditions. Consistently, DDA1 deficiency markedly impaired glioblastoma growth and induced compensatory upregulation of metabolic activity.

Conclusion

Our findings identify DDA1 as a previously unrecognized phosphorylation target downstream of mTORC1 and a critical mediator of the mTORC1 driven DNA damage response. Through its involvement in DNA repair and metabolic gene regulation, DDA1 appears to support glioblastoma progression, providing mechanistic insight into mTORC1 related gliomagenesis and suggesting potential therapeutic relevance.