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Homeodomain-containing protein PRRX1 senses DNA double-strand breaks and anchors the Ku heterodimers to promote non-homologous end-joining

GSE265857 Mus musculus Expression profiling by high throughput sequencing 6 samples Submitted 2025/03/26 Platform GPL24247
Summary
The DNA-PK complex is essential for non-homologous end-joining (NHEJ) to repair DNA double-strand breaks (DSB) in a template-independent way. The association of Ku70/80 with the DSB ends facilitates the formation of the DNA-PK holoenzyme. Many questions remain regarding the dynamics that DNA-PK is attached and stabilized at broken DNA ends. Here we revealed that PRRX1, a homeodomain containing protein, mediates chromatin localization and subsequent activation of the DNA-PK. PRRX1 oligomerizes to enable its simultaneous associations with both double-strand DNA and the SAP domain of Ku70, thereby enhancing Ku anchoring at DSBs to stabilize DNA-PK for efficient NHEJ repair. Low expression and pathogenic mutations of PRRX1 are associated with genomic instability and defective NHEJ repair. The peptide interfering PRRX1 oligomerization compromises NHEJ and hampers cell survival on irradiation. These findings deepen our understanding of how the NHEJ machinery is activated and have implications for optimizing cancer therapies.
Published in
Homeodomain protein PRRX1 anchors the Ku heterodimers at DNA double-strand breaks to promote nonhomologous end-joining
Wang Y, Shen F, Zhao C et al. · Nucleic acids research 2025 · PMID 40114375 · doi:10.1093/nar/gkaf200
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Also filed as BioProject PRJNA1104553 and SRA study SRP504092. Searching any of these in the dataset finder brings you back here.

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