Palmitate-activated IRE1-XBP1 signaling limits DNA damage and is associated with H2A.X-linked DNA damage response transcripts in triple-negative breast cancer cells
Palmitate-associated lipotoxic stress activates the endoplasmic-reticulum stress sensor protein IRE1, but how IRE1 signaling influences genotoxic-stress responses in triple-negative breast cancer remains unclear. Here, we investigated IRE1 and XBP1 signaling in MDA-MB-231 cells exposed to palmitate and etoposide. Under combined lipotoxic and genotoxic stress, XBP1 depletion increased DNA-damage…
Palmitate-induced lipotoxic stress triggers a protective signaling pathway in triple-negative breast cancer cells, involving the endoplasmic-reticulum stress sensor protein IRE1 and its downstream effector XBP1. When exposed to both lipotoxic and genotoxic stress, IRE1 activation reduces DNA damage accumulation, while XBP1 depletion exacerbates it.
The study found that pharmacologic inhibition of IRE1 RNase activity heightened DNA damage following etoposide treatment, suggesting that IRE1's RNA-degrading function is crucial for maintaining genomic integrity. IRE1 status, along with XBP1 manipulation, had contrasting effects on the abundance of H2A.X and {gamma}H2A.X, indicating context-dependent regulation of chromatin-associated DNA-damage signaling.
At the RNA level, IRE1 mediated the recruitment of H2A.X and the enrichment of H2A.X-linked DNA-damage-response transcripts HUWE1 and BRCA2. These findings suggest that palmitate-activated IRE1-XBP1 signaling is involved in genome-protective responses during genotoxic stress and highlight a network of IRE1-associated DNA-damage-response transcripts in triple-negative breast cancer cells. However, the direct cleavage of these transcripts by IRE1 remains to be determined.
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