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<p>BRCA1, a well-known tumor suppressor, maintains genomic integrity by facilitating homologous recombination (HR) repair and protecting DNA replication forks. However, its roles beyond DNA repair and replication remain largely unexplored. Here, we demonstrate that BRCA1 interacts with the RNA-binding protein PARP13 in the cytoplasm of ovarian cancer cells, with DNA damage enhancing this interaction via DNA-PK. Notably, BRCA1/PARP13 association is essential for cell survival but does not influence DNA repair efficacy following DNA damage. Mechanistically, PARP13 binds and destabilizes the mRNA of the endoplasmic reticulum (ER) membrane protein SEC61G. Upon DNA damage, BRCA1 disrupts PARP13-mediated SEC61G mRNA decay, leading to SEC61G upregulation. Elevated SEC61G levels cause calcium leakage from the ER into the cytosol, activating the pro-survival kinase Akt. These findings identify the BRCA1-PARP13-SEC61G axis as a non-canonical DNA damage response (DDR) pathway and highlight mRNA stability and ER calcium signaling as potential therapeutic targets to overcome chemoresistance.</p><p></p>

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Non canonical BRCA1 promotes cell survival via modulating PARP13-mediated SEC61G mRNA decay

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月6日

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  • Binghe Sun,
  • Yuting Li,
  • Yue Wu,
  • Cong Wang,
  • Jiawei Zhu,
  • Wanying Zhang,
  • Dake Li,
  • Wancai Que,
  • Guo Chen

摘要

BRCA1, a well-known tumor suppressor, maintains genomic integrity by facilitating homologous recombination (HR) repair and protecting DNA replication forks. However, its roles beyond DNA repair and replication remain largely unexplored. Here, we demonstrate that BRCA1 interacts with the RNA-binding protein PARP13 in the cytoplasm of ovarian cancer cells, with DNA damage enhancing this interaction via DNA-PK. Notably, BRCA1/PARP13 association is essential for cell survival but does not influence DNA repair efficacy following DNA damage. Mechanistically, PARP13 binds and destabilizes the mRNA of the endoplasmic reticulum (ER) membrane protein SEC61G. Upon DNA damage, BRCA1 disrupts PARP13-mediated SEC61G mRNA decay, leading to SEC61G upregulation. Elevated SEC61G levels cause calcium leakage from the ER into the cytosol, activating the pro-survival kinase Akt. These findings identify the BRCA1-PARP13-SEC61G axis as a non-canonical DNA damage response (DDR) pathway and highlight mRNA stability and ER calcium signaling as potential therapeutic targets to overcome chemoresistance.