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Oncogenesis

Oncogenesis

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

Published:6 October 2025 DOI: 10.1038/s41389-025-00578-x PMID: 41052987
Binghe Sun,?Yuting Li,?Yue Wu,?Cong Wang,?Jiawei Zhu,?Wanying Zhang,?Dake Li,?Wancai Que,?Guo Chen

Abstract

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. The schematic illustrates the mechanism by which non-canonical BRCA1 promotes cell survival through regulating PARP13-mediated SEC61G mRNA decay. Under DNA damage-free conditions (left panel), SEC61G maintains cellular calcium homeostasis between the endoplasmic reticulum and cytosol to support normal physiological functions. Upon DNA damage induction (right panel), enhanced interaction between BRCA1 and PARP13 attenuates the mRNA degradation activity of PARP13 toward SEC61G, leading to upregulated SEC61G protein expression. The aberrant accumulation of SEC61G triggers endoplasmic reticulum calcium leakage, which subsequently activates the AKT signaling pathway to enhance cell survival capacity.

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Procduct Name CAS Molecular Formula Supplier Price
(+)-Camptothecin 7689-03-4 C20H16N2O4 749 suppliers $9.00-$1900.44
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